sepsis case study uk

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A 26-year-old female arrives with a companion to an urgent care at 0845 by personal vehicle for treatment of suspected foot infection. The patient’s companion (a female roommate) reports to the triage nurse that the patient cut her foot while wading in the ocean over the weekend. They did not initially notice the cut but discovered it while removing tar from the bottom of the right foot. Approximately 24 hours later, her foot became too painful for ambulation, and a “thick, yellowish” discharge began to drain from the cut. Vitals upon arrival at urgent care showed a temperature of 101.5F, heart rate of 130, respiratory rate of 24, and blood pressure of 86/40. Her pain was 9/10 in her right foot and described as throbbing. During a HTT assessment by the PA, the patient is reported to be arousable to voice, oriented to person and place only, and complaining of nausea. The patient reports she took Tylenol that morning to relieve pain and fever. Her skin is pale, diaphoretic, and hot.

The urgent care calls 911, and medics are dispatched to the center for transfer to the local hospital to treat the patient for suspected sepsis. Upon arrival, medics find the patient is still tachycardic, and that her blood pressure has dropped to 80/40. Her respiratory rate has increased to 30. During transport, medics insert a 20 gauge peripheral IVs in the patient’s left antecubital. They infuse a fluid bolus of 500 mL of normal saline to manage her patient’s hypotension, and administer oxygen by simple mask at 4L/min. During the primary assessment, the patient’s right foot reveals a two-inch laceration with no active bleeding that is erythematous, edematous (non-pitting), and radiating heat. Edema is covering the entire bottom of the right foot and extends to the patient’s ankle.

The patient arrives to the emergency room within 15 minutes and is admitted for treatment at 1000. On the unit, Code Sepsis is called, and the agency’s sepsis protocol based on the Surviving Sepsis campaign is implemented. The patient’s vitals are now a temperature of 102F, heart rate of 140, respiratory rate of 34, and blood pressure of 96/42. Lactate levels are immediately measured. A second 20 gauge peripheral IV is inserted into the right antecubital, blood cultures are drawn, and a swab sample is taken of the cut and submitted to the laboratory for a culture and sensitivity test. Broad spectrum antibiotic ceftriaxone (Rocephin) is administered, and patient is given Ibuprofen to manage her fever. The patient is diagnosed with septic shock, and because she is still hypotensive, 30mL/kg of normal saline is infused. The patient’s lactate levels come back as 2.4 mmol/L. Norepinephrine (Levophed) is also hung, and the patient is further monitored. With careful titration and vital monitoring, the use of vasopressors restores the patient’s blood pressure to 101/52. Although fluid resuscitation helps to bring the patient’s heart rate down to 104, Nicardipine (Cardene) was ordered in anticipation of further needs to manage tachycardia. The patient is transferred to the ICU at 1300 for further monitoring and management of her hemodynamic status.

In the ICU, the patient’s vitals stabilize. Her tachypneic state reduces, and respiratory rate is now 18. She no longer requires oxygen supplementation. Her pain is being managed with IV morphine and she rates the pain in her as 3/10. Her IV pump is running 125 mL an hour of normal saline along with piggybacked ceftriaxone (Rocephin), and labs return a lactate level of 1.5 mmol/L. The patient’s roommate arrives. She is tearful and explains to the ICU nurse that she wanted to tell the patient’s parents what happened, but the patient refused. The ICU nurse calls for the case manager and a social service consult to inquire further. The patient’s roommate explains to the interdisciplinary team that the patient does not have insurance because she is 26 and has been removed from her parents’ medical plan. The parents are also currently engaged in a divorce, do not speak to each other, and use their daughter to communicate. The patient is aware of their financial situation and her lack of medical coverage and does not want to worry her parents in spite of her critical medical state.

• What are the priority nursing interventions for this patient in the ICU setting?
• What signs and symptoms in this patient would indicate the need for mechanical ventilation?
• What is the nurse’s role in addressing the patient’s financial concerns?

References:

Gordon, A.C., Mason, A.J., Thirunavukkarasu, N., et al. (2016). Effect of early vasopressin vs norepinephrine on kidney failure in patient with septic shock: The VANISH randomized clinical trial. JAMA, 316 (5), 509–518. doi:10.1001/jama.2016.10485

Hinkle, J. L., & Cheever, K. H. (2014). Brunner & Suddarth’s textbook of medical-surgical nursing. Philadelphia: Lippincott Williams & Wilkins. PulmCCM. (2019, January 14). From the Surviving Sepsis Guidelines: Criteria for diagnosis of  sepsis. Retrieved from https://pulmccm.org/review-articles/surviving-sepsis-guidelines-criteria-diagnosis-sepsis/

Schmidt, G.A., & Mandel, J. (2019, March). Evaluation and management of suspected sepsis  and septic shock in adults. Retrieved from https://www.uptodate.com/contents/evaluation-and-management-of-suspected-sepsis-and-septic-shock-in-adults?search=sepsis treatmentadult&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H465649907

Society of Critical Care Medicine. (2019). Hour-1 bundle: Initial resuscitation for sepsis and  septic shock. Retrieved from http://www.survivingsepsis.org/SiteCollectionDocuments/Surviving-Sepsis-Campaign-Hour-1-Bundle.pdf

Zhang, M., Zheng, Z., & Ma, Y. (2014). Albumin versus other fluids for fluid resuscitation in patients with sepsis: A meta-analysis. PloS one , 9 (12), e114666.

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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“ THINK SEPSIS ” is a Health Education England programme aimed at improving the diagnosis and management of those with sepsis.

A number of sepsis cases result in death every year.  Some of the deaths are preventable. Prompt recognition of sepsis and rapid intervention will help reduce the number of deaths occurring annually.

The learning materials that are available on this website support the early identification and management of sepsis.

This website has a film and a wide range of learning materials for primary care, secondary care and paediatrics.

For more information on HEE’s work on sepsis please visit our  website .

Identifying and managing sepsis in primary care is an important measure in reducing deaths.

70% of sepsis cases develop within primary care. This sepsis in primary care elearning module addresses the high risk areas for the early identification and management of sepsis.

The first session is aimed at all clinical staff that work in primary care, giving an overview of sepsis for all staff in primary care. The remaining sessions on diagnosing sepsis in adults, children, elderly and complex issues such as maternity and neutropenia are primarily aimed at General Practitioners.

The elearning  module , consists of the following five sessions:

• Session 1 – Overview of Sepsis
• Session 2 – Adult Sepsis
• Session 3 – Childhood Sepsis
• Session 4 – Complex Sepsis Issues and Future Development
• Session 5 – Sepsis, Care Homes and the Frail Elderly

The Royal College of General Practitioners (RCGP) has developed a  sepsis toolkit  to support GPs and healthcare professionals to identify and manage the condition in patients. This toolkit has been designed to help GPs and other healthcare professionals in primary care tackle this challenge with a series of educational materials, up-to-date guidance and training resources. This also includes  10 Top Tips  for GPs & Primary Healthcare Clinicians to support a sepsis aware consultation.

Reception staff are commonly the first point of contact for people with acute health needs. Receptionists are not expected to make clinical decisions but need to be aware of which symptoms or presentations might suggest the patient is acutely unwell and requires specific actions. This programme has been developed to support receptionists in recognising specific symptoms that may indicate a deteriorating patient, including sepsis, and how they would consider escalating this to a clinician within the service/practice in which they operate.

The Leadership in Primary Care module is designed for non-clinical and clinical leaders working in primary care and looks at the challenges in leadership roles, to ensure best practice, in identifying and managing acute deterioration and sepsis in Primary Care settings, including general practice.

Improving Early Detection & Treatment of Sepsis

Approving Quality Alliance (AQuA) in partnership with HEE has developed a series of case studies to support the education of sepsis and deterioration in adults.

These case studies have been written in support of the Second Cross-System Sepsis Board Action Plan theme ‘Celebrating achievements and good practice’. The collection is designed to provide healthcare staff with examples of initiatives to improve the recognition of, and response to, sepsis in a range of settings. These case studies promote a collaborative approach, to improve how quickly staff can recognise and treat people with sepsis.

Each case study includes sections on key learning and reflection points, with a clear statement of what the team learned during the course of the improvement project. Measurement data is also provided to help learners identify improvement opportunities in the treatment of people with sepsis and monitor the impact of interventions.

You can access all the case studies in one document – Patient Pathway & System Solutions on Sepsis – All case studies, or you can access specific areas – Primary Care, Secondary Care, Cross sectional network and Diagnostics. Screening tools and observation charts are provided, along with 3 films to support the training.

Project Transform

An innovative interactive film,  Project Transform , which helps all healthcare professionals understand the common factors that may delay or hinder the diagnosis and treatment of sepsis, and therefore spot and treat sepsis earlier is also available. Created by the Royal Surrey County Hospital NHS Foundation Trust in conjunction with The Health Foundation, the UK Sepsis Trust and HEE, the film explores the features that make the diagnosis of sepsis difficult, the use of safety netting and empowering the most junior members of the team. We hope that this film will increase awareness of sepsis and the signs, to help staff diagnose and treat sepsis earlier.

Getting it Right

HEE in its report ‘Getting it right – the current state of sepsis education and training for healthcare staff across England’ ( Exec Summary and Full Report ), highlights numerous examples of good practice in relation to sepsis education and training. This report lists a number of resources that would be beneficial to healthcare workers requiring training on sepsis, and the audience they are most applicable to. Examples of learning sessions that healthcare workers in secondary care will find useful to address their training needs can be found below:

• Assessment and Differential Diagnosis of Sepsis (03_17_01) E-learning for Doctors and nurses in secondary care
• Management of the Septic Patient (03_034) E-learning for Doctors in secondary care. Nursing and pharmacy staff in a critical care environment
• Managing Sepsis (08_09) E-learning for Foundation programme doctors.

The UK Sepsis Trust has developed learning resources that supports the training and education of all healthcare professionals on how to diagnose and treat sepsis effectively.

Sepsis for management and executive staff in acute care

A learning resource for executive, non-executive and management level staff in trusts on sepsis, incorporating antimicrobial resistance and stewardship.

This training programme gives specific context for boards to understand the clinical priorities within healthcare and how boards and clinical leaders can work together to deliver of high quality safe care.

The training consists of an elearning session to be taken independently, to be followed by a facilitated discussion with board members and clinical staff.

It encourages engagement and debate within a trust, to understand locally what appropriate care looks like and what a board should be doing to deal with specific issues within their trust to maintain good standards on the quick recognition, management and treatment of sepsis and in improving standards of antibiotic prescribing.

Sepsis can strike the very old and the very young and as a result children, particularly premature babies and infants, can be more susceptible to developing sepsis.

Everyday somewhere in the UK a child dies from sepsis and cases have shown that a significant number are preventable. Children who survive can be left with debilitating consequences.

Early recognition and intervention can improve outcomes for infants and children with conditions that lead to sepsis. These paediatric resources are designed to ensure that all of us who work with sick children on the front line know how to recognise the clinical features of sepsis at the earlier stages and what to do when we see it.

An introductory resource aimed at all healthcare workers

This film explores the key points to consider in diagnosing and managing sepsis and refers to a patient story, presented by the parents of Maude Watkins who died of sepsis aged three.

Maude’s parents Jason (who is an actor in real life) and Clara share their experience of the traumatic loss of their daughter to sepsis, and provide a useful point of reflection for healthcare professionals on how they can ensure the appropriate and prompt recognition and management of sepsis in children. Their story also provides an important insight and reflection on the impact on families from the death of a family member. The film is an entry point to resources that paediatricians and GPs are recommended to look at relating to sepsis in children.  

An extended resource aimed at all clinical workers

This case based guide is aimed at supporting clinicians in the recognition and treatment of sepsis in children and involves the stories of three children, their assessment, experiences and treatment.

The learning sessions provide important insights in the recognition and management of sepsis in children. The sessions include the general principles for the safe assessment of a sick child, components of the consultation and assessment, specific factors to be considered in primary and secondary care settings and interpretation of investigations amongst others.

The training materials can be used in face to face teaching sessions or independently as elearning, in bite sized chunks to allow you to go at your own pace. The training is supported by a course summary sheet and a workbook that can contribute to a learner’s continuous professional development (CPD).

Paediatric sepsis podcasts

We worked with RCPCH to produce paediatric sepsis podcasts, that are designed as educational resources for health and social care professionals.

They explore what sepsis is, the complexities of how to recognise and manage sepsis, what is different about sepsis in children with complex health conditions and offers real-world advice and guidance on how to manage paediatric sepsis.

Practical resources for clinicians to share with patients and carers (as part of safety-netting) – home setting

Nhs choices:.

• Looking after a sick child : aimed at parents (NHS Choices)
• Does your child have a serious illness?  Aimed at parents (NHS Choices)
• Patient UK – Symptom Checker
• Health Help Now app  (specific localities only) or for the App
• BabyCheck  (App)
• Wessex Parent information : aimed at parents with children aged 6 months to 5 years
• UKST Spotting sepsis in children leaflet – Sepsis Assessment and Management (SAM)
• NHS Choices Spotting sepsis in under 5’s

Practical resources for clinicians to share with patients and carers (as part of safety-netting) – hospital / secondary care

Recognition of early sepsis .

• UKST  – Sepsis card
• MRF : Algorithms for Management of Meningococcal Disease and Bacterial Meningitis in Children and Young People
• KSS Parent info sheets for sick children – elfh or  SESCN

Recognition of early sepsis – assessment of sick children

• SystemOne templates  – Dr David Gould and Cricketfield practice
• KSS Clinical Pathways for Sick Children – elfh or SESCN

Educational resources for healthcare workers – primary care

Consultation matters.

• Re-ACT  Talks : The Effect of Criticism on Parents with Sick Children by Dr Sarah Neill
• Re-ACT Talks : Deterioration: How to Spot the Sick Child by Dr Ffion Davis
• Spotting Sick Child toolkit
• NICE RAG  assessment tool / traffic light system for identifying the risk of serious illness in children
• RCGP  elearning feverish child
• KSS Deanery – elfh elearning resource (clinical pathways for sick children)
• Human Reliability in Primary Care  by Dr Dawda
• UKST G.P. Paediatric Sepsis Decision Support Tool
• UKST Prehospital Sepsis Screening and Action Tool

Safety-netting

• NICE  – feverish child templates
• NICE algorithm for managing suspected sepsis in children aged under 5 years outside an acute hospital setting
• NICE risk stratification table for under 5 years with suspected sepsis
• NICE combined algorithms and risk stratification tables for those with suspected sepsis (includes for those under 5 years)
• UKST GP Paediatric Sepsis Decision Support Tool

Recognition of early sepsis

• Re-ACT Talks : Spotting Sepsis in the Sick Child by Dr Jeremy Tong
• Northern Paediatrics  – Northern Paedatric Sepsis

Sepsis pathways

• RCPCH elearning  – meningitis and meningococcal septicaemia
• Spotting the Sick Child
• NICE algorithm for managing suspected sepsis in children aged under 5 years in an acute hospital setting
• UKST ED/AMU Paediatric Sepsis Screening & Action Tool
• UKST Inpatient Paediatric Sepsis Screening & Action Tool

The Learning Disabilities Mortality Review (LeDeR) report published in May 2018 highlighted sepsis as a key contributor to premature mortality, with 11% of deaths being recorded as sepsis related. In response NHS England have undertaken work to improve the sharing of information on people with a learning disability, across health and care settings and have published an ‘ action from learning ’ report that provides examples of the local changes that have been made to services in response to common themes raised through LeDeR reviews across the country.

A number of freely available resources have been developed for the system that includes:

• a sepsis song to raise awareness and improve vigilance to the signs of sepsis amongst people with a learning disability.
• a training film that supports health and care professionals, and carers, to spot the softer signs of deterioration in people with a learning disability.
• a training film aimed at those who care for people with a learning disability who may not be able to communicate or verbalise how they are feeling.
• a film aimed at people with a learning disability who may not be able to communicate or verbalise how they are feeling.
• a podcast on recognising deterioration and sepsis amongst people with a learning disability, which may also be useful for carers.

Antonio De Gregorio

Mohamed Sadak

Janet Flint

Dr Gary Wares

Dr Neil Ralph

Andi Blackmore

Simon Stockley

Alison Tavaré

James Larcombe

Dr Nelly Ninis

Dr Tim Fooks

Dr Matt Inada-Kim

Available to all.

The Sepsis  programme is freely available to access here . Please note your progress and completion of sessions will not be recorded and you will not be able to generate a record of completion. If you require evidence of learning, please register and then log in to access this programme on the elfh Hub.

If you already have an account with elfh, then you can enrol on to the Sepsis   programme by logging in to the elfh Hub, selecting My Account > Enrolment and selecting the programme. You can then access the programme immediately in the My elearning section.

Register >

To view the Sepsis   programme, select the View button below. If you already have an account with elfh, you will also be able to login and enrol on the programme from the View button.

NHS healthcare staff in England

The Sepsis  programme is also available to NHS healthcare staff via the Electronic Staff Record (ESR). Accessing this elearning via ESR means that your completions will transfer with you throughout your NHS career.

Further details are available here .

Not an NHS organisation?

If you are not an NHS health or care organisation and therefore do not qualify for free access elfh Hub, you may be able to access the service by creating an OpenAthens account.

To check whether or not you qualify for free access via OpenAthens, you can view the eligibility criteria and register on the ‘ OpenAthens ’ portal.

Care home or hospice staff

To register for the Sepsis  programme, select the ‘ Register ’ button above. Select the option ‘I am a care home or hospice worker’ then enter your care home / hospice name or postcode and select it from the options available in the drop down list. Finally enter your care home / hospice registration code and select ‘Register’. You may need to see your employer to get this code.

If your employer does not have a code, then they need to contact the  elfh Support Team . The Support Team can either give the employer the registration code or arrange a bulk upload of all staff.

Detailed instructions on how to gain access are available here .

Social care professionals

Access to elfh content is available to all social care professionals in England whose employers are registered with the Skills for Care National Minimum Data Set for Social Care (NMDS-SC). Every employer providing NMDS-SC workforce information to Skills for Care has been given a user registration code for their staff. This code enables you to self-register for access to the Care Certificate programme. Please contact your employer for more details about the registration code.

For information about registering your organisation with the NMDS-SC your employer should access  www.nmds-sc-online.org.uk  or contact the Skills for Care Support Service on 0845 8730129.

If you have a registration code, you can register by clicking  here

Registering large numbers of users

If you are a HR, IT or Practice Manager and would like to register and enrol large numbers of staff within your organisation for access onto the Sepsis   programme, please contact elfh directly.

Organisations wishing to use their own LMS

For HR departments wanting to know more about gaining access to courses using an existing Learning Management System please contact elfh directly to express interest.

More information

Please select the following link for more information on how to use the elfh Hub .

Project Sepsis

Project Sepsis is a research collaboration across medicine and science disciplines that addresses an urgent medical need for recognising and accurately detecting infection underlying sepsis - “blood poisoning” - in extremely vulnerable populations of the very young and old.

Video of Professor Peter Ghazal talking through the work of Project Sepsis.

Symptoms can be subtle, yet if sepsis goes undetected, catastrophic loss of life can occur within hours if not prescribed antibiotics. Consequently there is an overuse of antibiotics that can lead to antimicrobial resistance, itself a global health threat. The sensitivity of current tests is poor with between 6 to 8 cases out of 10 being missed.

Project Sepsis uses computer-assisted genome, proteome, and metabolism approaches to decode the communication from the blood-immune system to more rapidly detect infection and identify innovative treatments.

Project Sepsis is part-funded by the European regional Development Fund through the Welsh Government.

If you would like to find out more about project sepsis please contact: [email protected]

Project Sepsis is part of a collaboration with Dr C Costello’s team at Imperial College which recently secured National Institute for Health Research (NIHR) funding for a project tilted: Digital alerting to improve sepsis detection and patient outcomes in NHS Trusts.

Through this collaboration, the Project Sepsis team facilitated that our research partner, Cardiff and Vale University local health board, become a member of the NIHR Health Informatics Collaborative (HIC) data sharing framework.

This will support the establishment of a sustainable clinical informatics infrastructure at the trust in line with those at other participating HIC centres, create a shared governance framework and enable collaborative clinical research projects across the HIC, with all centres involved in relevant collaborations and initiating expansion to future data collaborations.

Celebration of achievement

Project Sepsis was funded by the Welsh Government’s Sêr Cymru programme. Prof Peter Ghazal was appointed Sêr Cymru Chair in Systems Medicine, Systems Immunity Research Institute, and established Project Sepsis in December 2017 to strengthen sepsis and systems research within Cardiff University and Wales. The project has produced high quality and impactful research, with substantive progress being made in the fight against Sepsis and improving sepsis awareness with the Sepsis Trust UK, and management and diagnosis, while increasing research capacity and our understanding of what drives this condition.

Project Sepsis applied a community-in-action approach uniquely establishing a Sepsis Engagement Centre housing the “Goldilocks Ward” used for promoting public and patient involvement, training and research. We successfully appointed at an early stage a lay advisory group, and over 20 research staff and 8 research students including 2 new lectureships that actively contributed to the project, and have strengthened collaborations with existing partners while building national and international research networks and links with new strategic partners from multi-disciplinary teams across academy and industry. This includes: Introduction of a sepsis case study to the medical curriculum, working with industry to develop a 360 degree fully immersive virtual reality training resource for medical students and staff, mathematical models for understanding and predicting sepsis, validating and developing new diagnostic tools and tests. Across three of our clinical platforms (neonatal, maternal and paediatric sepsis studies) we gratefully received blood samples from approximately 1000 participants in our research at Cardiff and Vale University Hospital and almost similar contribution from our partnering centres. This was during very challenging circumstances during the pandemic, allowing us to establish a large biobank of samples for continued research, while building key relationships with our clinical teams across various specialities in the NHS.

We are now beginning to see an increase in scientific out puts and collaborations with other UK based and international institutions.  Our research and technical achievements of Project Sepsis, could not be accomplished without participation of public and patient involvement. Improved public awareness of sepsis is key and we are proud of our contributions to a variety of successful engagement events highlighting differing aspects of sepsis and including yearly seminars to mark World Sepsis Day.  As a whole community we have increased the development of excellence research capability in Wales within systems medicine, and although the European sponsored Ser Cymru programme ends in April 2023, Project Sepsis will continue with the next phase of decoding sepsis and continue to build on our achievements.

Prof Peter Ghazal was recognised in the New Year’s Honours 2023 and awarded an OBE for his services to systems immunology.

Key research themes

(see Figure 1)

• Maternal sepsis (mSEP)
• Neonatal sepsis (nSEP)
• Paediatric sepsis (pSEP)
• Adult sepsis (aSEP)

Areas of expertise

Core project sepsis team, prof peter ghazal (n,p,asep) - chief investigator and academic lead for n, psep.

I previously led the Division of Pathway Medicine at the University of Edinburgh.

Watch a video of me talking about the research I carried out into Neonatal Medicine whilst there .

My research interests are aimed towards understanding how host-gene networks control infection, especially with those host-pathways associated with sepsis and the immune-metabolic axis. My recent studies have pioneered the field of host genomics of early-life infection, mapping and deciphering gene metabolic signatures of systemic host response to infection in pre-term infants and neonates and understanding the molecular wiring and mechanisms for coupling lipid metabolism to immune (interferon) response.

These studies are specifically aimed at the development of new diagnostic and therapeutic strategies, including predictive modelling of host-defence against infection in sepsis, and the development of new computational and functional genomic methods for gaining a deeper understanding of complex dynamical biological systems of viral (cytomegaloviral) and microbial diseases.

Prof Valerie O’Donnell (n,p,aSEP) - Principle Investigator and academic lipid metabolism lead

Our current research is focused on understanding the role of lipids (fats) in vascular inflammation, a major complicating factor in sepsis and driver of multi-organ failure. Lipids are generated by circulating blood cells and platelets in response to blood infection. These stimulate clotting and cell damage, and dampening these processes while allowing the body to control the infection itself is a major goal of our research.

We have identified large numbers of new lipids made in blood cells and understanding their biological functions is a core research goal. Delineating how lipids and energy metabolites interface during sepsis to control inflammation and blood clotting is essential if we are to develop new prevention and treatment approaches.

Dr Robert Andrews (n,p,aSEP) - Informatics lead

My interests are in the information management and analysis of large biomedical datasets. As part of my role, I design and build compute infrastructure for handling high-throughput ‘big-data’. Specifically, project sepsis will deploy a biomedical informatics framework for the capturing, querying, retrieval and sample tracking of clinical and laboratory research information with which to automate and manage novel microfluidic approaches aimed toward advancing innovative precision diagnostic tests and treatments for sepsis.

I also teach chromatin informatics with the Wellcome Trust advanced courses and lead the omics module on the MSc in Bioinformatics at the University.

Sarah Edkins

Dr daniel white - senior innovation and technology scientist.

With over 20 years of experience in lipid biology and analytical chemistry, spanning scientific fields from environmental monitoring to biomedical research, my role role in Project Sepsis is to develop high-throughput lipidomic profiling strategies to determine robust biomarkers of sepsis in the systemic circulation of patients. These methods are part of integrative strategy for understanding the casual link between metabolism and the immune response in determining sepsis patient outcome and together with clinical team members will be translated to the clinical care pathway for improving precision in identifying and treating those patients presenting with suspected sepsis.

Dr James McLaren - Sêr Cymru Lecturer in Systems Immunity

My research interests focus on understanding how adaptive immune responses (T cell driven) are mobilised during viral (HIV, cytomegalovirus) and microbial infections, inflammation and disease. Furthermore, I have a keen interest in discovering how this type of cellular immunity is regulated by biological signals (cytokines) and how it can destabilise when global immune responses become imbalanced, such as in sepsis. As part of Project Sepsis, my aim is to deconvolute the immunological mechanisms that drive the suppression of adaptive immunity in sepsis with a view to help improve diagnosis and to inform the design of novel therapeutic interventions.

Dr. Nicos Angelopoulos - Sêr Cymru Lecturer in Computational Systems Immunity

I work on knowledge based systems for explainable AI in biology and medicine. A computer scientist by training, I worked on methodological aspects of probabilistic programming before developing a strong interest in knowledge-based data analytics in bio-medicine. Of particular interest is the representation of biological knowledge in the context of machine learning both in how prior knowledge can incorporated in the learning process, but also in how we can learn models of interpretable knowledge. Bayesian approaches to model learning are of particular interest, especially when combined with classical AI approaches of knowledge representation amalgamating logic and probability theory. I also have interests in open source software and the ethical use of AI, contributing a number of libraries to the SWI-Prolog, logic programming system.

Dr Luke Davies

I am a passionate scientist with a research background in innate immune cell biology and metabolism. Sepsis is a life-threatening condition driven by dysregulated immunity which results in organ failure and metabolic dysfunction. I am excited to work with Project Sepsis to investigate new diagnoses and treatments for sepsis.

Dr. Patricia Dos Santos Rodrigues

Dr jason twohig - lecturer in medical transcriptomics.

I utilise novel ‘OMICs’ approaches to facilitate the identification and stratification of patients with chronic disease for effective therapeutic treatment with biologics. I am particularly interested in identifying blood transcriptomic signatures which predict the presence of SEPSIS, its progress, its mechanism, and its resolution. More broadly, my research interests also include understanding the role of cytokines in inflammation and homeostasis in the immune and neurological system during development and infection.

Dr Widad Dantoft (n,p,aSEP) - Research Associate

My research interest lies in understanding the intricate interplay between immunity and metabolism in the presence of viral (CMV) and bacterial infections, and how this affects the infection process and outcome. I am in particularly interested in how this immune-metabolic interplay is regulated on a transcriptional level.

Dr Mallinath Chakraborty (nSEP) - Clinical lead

My interests are in neonatal respiratory medicine and sepsis. I am the local Principal Investigator for several multi-centre clinical trials and am developing my own research group. I also run the respiratory module of the Masters in Neonatal Medicine at Cardiff University.

Dr Summia Zaher (mSEP) - Clinical lead

Dr tamas szakmany (asep) - clinical lead.

In collaboration with Public Health England and industry (Randox and Atlas Genetics) I have led Innovate UK funded multicentre clinical trials on adult sepsis. These studies identified mRNA and protein biomarker panels that distinguish sepsis from non-infective origin of organ dysfunction for use with point-of-care devices.

I further designed and led an award winning (Cardiff University Excellence in teaching award 2017 and NHS Wales Award runner-up 2016) collaboration with the Cardiff University Research Society for medical students, establishing the burden of sepsis on the general wards and Emergency Departments in Wales. These multi-centre point-prevalence studies recruited over 1000 patients quantifying the incidence when using different clinical scores to define sepsis.

Dr Siva Oruganti (pSEP) - Clinical lead

My background is a Bachelor in Medical Biology and a Master in Biomedicine. What fascinates me most is how complex systems in the body are regulated and interact, especially the immune system and the gut microbiota. My PhD is focused on the G-Protein coupled receptor (GPR) 84. This receptor has only been discovered quite recently; it is present on various immune cells and binds medium chain fatty acids. These come (most likely) from breast milk in the neonatal context. The receptor thus connects metabolism and diet with immunity. Since its expression is upregulated during neonatal sepsis, we decided to investigate the role of GPR84-signalling during neonatal sepsis, the presence and effects of its ligands and their potential origins. Hopefully this project will further the understanding of sepsis leading to better diagnosis and treatment in the future.

Simran Sharma

I am very excited to be joining project sepsis as a clinician as I see the detrimental impact of sepsis on mothers and babies every day. An opportunity to learn more through research is something I am very much looking forward to.

Dr Fergus Hamilton

Freya shephard, other collaborators and affiliated team members, dr claire smith (nsep) - edinburgh.

My research interest is in neonatal infection with on-going involvement in studies in this area. I am actively involved in the local neonatal unit infection surveillance programme and have played a significant part in introducing a successful infection reduction programme to the neonatal unit.

Prof Timothy Walsh (n,pSEP) - Principle Investigator

I am director of BARNARDS, a BMFG funded project examining the burden of neonatal sepsis in Nigeria, Pakistan, Bangladesh, Rwanda and Ethiopia. I am also PI of DETER-XDR-China and CUT-SEC that examines the one health approach to studying AMR in China, Vietnam and Thailand.

I am an advisor on AMR to the United Nations, Médecins Sans Frontières and the Fleming Fund.

Prof B Paul Morgan - Principle Investigator

I am an expert in the complement system, a critical component of innate immunity and a powerful driver of inflammation. Dysregulation of the complement system has been implicated in sepsis and systemic inflammatory response syndromes; indeed, complement markers in blood have been used to predict and monitor these conditions. Critically, an emerging wave of anti-complement drugs may provide new ways of breaking the cycle of inflammation in patients with sepsis.

Dr Paul Morgan (aSEP) - Principal Investigator

As an Intensive Care consultant and the Lead Volunteer in Wales for the UK Sepsis Trust, sepsis makes up a substantial part of my work.

My interests in sepsis has led me to try to drive change in sepsis recognition and care outside the critical care environment, working with staff from primary and secondary care so that sepsis can be spotted early, enabling timely intervention and thereby reduce the need for critical care admission. Ultimately, my hope is that this will reduce not just mortality from sepsis but also the morbidity, which results in long-term health problems for sepsis survivors. I am a member of the steering committee and co-author of the papers that have been published from the Size of Sepsis in Wales and the Defining Sepsis in the Wards point prevalence studies.

Dr Matthias Eberl (aSEP) - Principle Investigator and Academic lead of aSEP

My interdisciplinary research aims to characterise early immune responses in acutely ill patients and define pathogen-specific signatures of cellular and soluble biomarkers ('immune fingerprints'). This work has direct implications for improved diagnosis and treatment of microbial infections including sepsis.

Dr Matthew Morgan (aSEP) - Clinical lead

Intensive care doctor, scientist, computer programmer, teacher and geek interested in machine learning, medical education and public engagement. My PhD used artificial intelligence to tease out “immune fingerprints” from different types of life-threatening infections.

I have spent time training in the UK, Australia and the military. Passionate about critical care medicine and intensive care research, I also work with the British Medical Journal to improve medical education, healthcare IT and research outcomes.

Rhian Thomas-Turner (n,p,aSEP) - R&D Operations Manager

I am the R&D Operations Manager for the Noah’s Ark Children’s Hospital for Wales. My role involves both the strategic and operational oversight of research within the Children’s Hospital and running the newly establish Children and Young Adults’ Research Unit.   The aim of the Unit is to act a hub for high quality Child Health research in Wales.

Dr Jenna Bowen - Lecturer, Cardiff School of Pharmacy and Pharmaceutical Sciences

My research interests lie in the field of sepsis and infection, with a particular focus on the development of bio-sensing systems to enable rapid diagnosis, patient stratification and personalisation of therapies. I enjoy working across disciplines and have established collaborations across life science and engineering / physical science disciplines as well as with end-users from the clinical, commercial and third sector in order to deliver fit-for-purpose technologies.

I am also a co-founder of a start-up company, Cotton Mouton Diagnostics (CMD), which is developing a diagnostic platform that can be deployed across a range of healthcare settings.

Dr Mario Labeta (aSEP) - Senior Lecturer

My current work focuses on the immunobiology of the Toll-like family of immune receptors (TLRs) as mediators of immune and inflammatory responses. Following our discovery of a soluble form of TLR2 (sTLR2) in blood that has anti-inflammatory capacity, we are evaluating whether plasma sTLR2 may be used as a biomarker for sepsis, as opposed to SIRS and other serious infections. In collaboration with a Welsh biotech company ( JRBiomedical, Glyndwr University ) we are developing a fast point-of-care test to determine plasma levels of sTLR2.

In further work we have identified TLR2-derived peptides capable of boosting the immune response of immunosuppressed sepsis patients ex vivo, and currently seeking to stratify sepsis patient subgroup(s) that may therapeutically benefit from our TLR-based peptide strategy.

Dr Philip Anyanwu - Lecturer in Public Health

I am an infectious disease epidemiologist with research interests in causal inferential analysis and investigating the mechanism of impact of interventions to address antimicrobial resistance and sepsis.

I have a specific interest in the development and evaluation of digital applications for the management of sepsis, especially in LMICs. I am a co-investigator of a project on maternal sepsis working with research partners from Imperial College London and the University of Ibadan Nigeria to develop a digital system for sepsis alert and monitoring ward movement in maternity patients in Nigeria.

Rebecca Milton - Research Associate - Trial Manager

My research interests lie within maternal and neonatal health and I have a strong interest in working in low- and middle income countries. I obtained my Masters in Public Health at Cardiff University whilst working within a microbiology research group in the Institute of Infection and Immunity, Cardiff University. To date, much of my research has been focused on neonatal sepsis in LMICs. I have been working with Project Sepsis looking immunological markers, risk factors and incidence of stillbirths in northern Nigeria with an additional focus on cultural belief and understanding around stillbirth. I am currently working on a PhD by publication focusing on maternal and neonatal health in LMICs.

A feasibility study of stillbirths in Kano, Northern Nigeria.

Stillbirth Feasibility Study - Video

Find out more about the study

Our international community

Professor tobias strunk (nsep) - clinical associate professor, centre for neonatal research and education (the university of western australia, perth, australia) and neonatal directorate, king edward memorial hospital (perth, australia).

My research interest is the immunological determinants of newborn
susceptibility to invasive bacterial infection and novel prophylactic
and therapeutic interventions to reduce disease burden, areas highly  relevant to the current proposal.

EU NeoVanc Project

Clinical trial assessing the dosage of vancomycin antibiotic in the treatment of late onset bacterial sepsis caused by vancomycin susceptible bacteria in neonates and infants aged under three months.

Breathing Together

A five year research and engagement programme exploring breathing and lung health in children.

The Theirworld Edinburgh Birth Cohort

A 25-year study to learn more about how being born too soon or too small affects people’s health in later life.

Digital Alerting for Sepsis (DiAlS)

The DiAlS study will investigate the impact of digital sepsis alerts on patient outcomes and staff activity in NHS hospital Trusts across England and Wales.

DISCOVER ( DI agnostic and S everity markers of COV ID-19 to E nable R apid triage) study

Focused on blood-based biomarkers and their ability to predict a patient’s disease course alongside demographic factors such as age, sex, frailty and other medical conditions.

Project members

• Prof Carlo Giaquinto (University of Padova, Head of Paediatrics AIDS centre, Italy)
• Profs Mike Sharland  (St. Georges, University of London, Head of Paediatrics, UK)
• Prof Paul Heath (St. Georges, University of London, Paediatric infectious diseases, UK)
• Prof EvelyneJacqz-Aigrain (Robert Debre Hospital, Head of Paediatric pharmacology, France)
• Prof Irji Lutsar (University of Tartu, Head of Department of clinical microbiology, Estonia)
• Prof. Baiardi (Consorzio per Valutazioni Biologiche e Farmacologiche, Director Biostatistics, Italy)
• Dr. Mark Turner (University of Liverpool, Consultant neonatologist, UK)
• Prof Peter Ghazal (University of Edinburgh & University of Cardiff medical schools, Chief investigator project-sepsis)

Publications

• Milton, R. et al. 2021. Establishing the safety of waterbirth for mothers and babies: a cohort study with nested qualitative component: The protocol for the POOL study.. BMJ Open 11 (1) e040684. ( 10.1136/bmjopen-2020-040684 )
• Milosevic, S. et al. 2020. Factors influencing water immersion during labour: qualitative case studies of six maternity units in the United Kingdom. BMC Pregnancy and Childbirth 20 (1) 719. ( 10.1186/s12884-020-03416-7 )
• Milosevic, S. et al. 2019. Factors influencing the use of birth pools in the United Kingdom: Perspectives of women, midwives and medical staff. Midwifery 79 102554. ( 10.1016/j.midw.2019.102554 )
• Dantoft, W. et al. 2017. Genomic programming of human neonatal dendritic cells in congenital systemic and in vitro cytomegalovirus infection reveal plastic and robust immune pathway biology responses. Frontiers in Immunology 8 1146. ( 10.3389/fimmu.2017.01146 )
• Zhang, J. et al. 2017. Machine-learning algorithms define pathogen-specific local immune fingerprints in peritoneal dialysis patients with bacterial infections. Kidney International 92 (1), pp.179-191. ( 10.1016/j.kint.2017.01.017 )
• Raby, A. et al. 2017. Toll-like receptors 2 and 4 are potential therapeutic targets in peritoneal dialysis-associated fibrosis. Journal of the American Society of Nephrology 28 (2), pp.461-478. ( 10.1681/ASN.2015080923 )
• Holst, B. et al., 2017. Soluble toll-like receptor 2 is a biomarker for sepsis in critically ill patients with multi-organ failure within 12 h of ICU admission. Intensive Care Medicine Experimental 5 (1)( 10.1186/s40635-016-0116-z )
• Hopkinson, J. B. et al. 2016. People with dementia: what is known about their experience of cancer treatment and cancer treatment outcomes? A systematic review. Psycho-Oncology 25 (10), pp.1137 -1146. ( 10.1002/pon.4185 )
• Liuzzi, A. R. et al. 2016. Unconventional human T cells accumulate at the site of infection in response to microbial ligands and induce local tissue remodeling. Journal of Immunology 197 (6), pp.2195-2207. ( 10.4049/jimmunol.1600990 )
• Courtier, N. et al. 2016. Cancer and dementia: an exploratory study of the experience of cancer treatment in people with dementia. Psycho-Oncology 25 (9), pp.1079-1084. ( 10.1002/pon.4212 )
• Raby, A. and Labeta, M. 2016. Therapeutic boosting of the immune response: turning to CD14 for help. Current Pharmaceutical Biotechnology 17 (5), pp.414-418. ( 10.2174/1389201017666160114095708 )
• Duffin, R. et al., 2016. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science 351 (6279), pp.1333-1338. ( 10.1126/science.aad9903 )
• Morgan, M. et al. 2016. Sepsis patients with first and second-hit infections show different outcomes depending on the causative organism. Frontiers in Microbiology 7 207. ( 10.3389/fmicb.2016.00207 )
• King, A. , Hopkinson, J. B. and Milton, R. 2016. Reflections of a team approach to involving people with dementia in research. International Journal of Palliative Nursing 22 (1), pp.372-377. ( 10.12968/ijpn.2016.22.1.22 )
• Dickinson, P. et al., 2014. Whole blood gene expression profiling of neonates with confirmed bacterial sepsis. Genomics Data 3 , pp.41-48. ( 10.1016/j.gdata.2014.11.003 )
• Eberl, M. et al. 2014. Pathogen-specific immune fingerprints during acute infection: The diagnostic potential of human γδ T-cells. Frontiers in Immunology 5 572. ( 10.3389/fimmu.2014.00572 )
• Davey, M. S. et al., 2014. Microbe-specific unconventional T cells induce human neutrophil differentiation into antigen cross-presenting cells. Journal of Immunology 193 (7), pp.3704-3716. ( 10.4049/jimmunol.1401018 )
• Smith, C. L. et al., 2014. Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nature Communications 5 4649. ( 10.1038/ncomms5649 )
• Raby, A. et al. 2013. Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens. Science Translational Medicine 5 (185) 185ra64. ( 10.1126/scitranslmed.3005544 )
• Cohen-Bendahan, C. C. C. et al., 2005. Is there an effect of prenatal testosterone on aggression and other behavioral traits? A study comparing same-sex and opposite-sex twin girls. Hormones and Behavior 47 (2), pp.230-237. ( 10.1016/j.yhbeh.2004.10.006 )

Dr James McLaren took part in an episode of the Discovery Matters podcast to discuss the role of single cell sequencing in detecting sepsis:

Discover Matters -  Detecting sepsis: the role of single-cell

Professor Peter Ghazal took part in an episode of the Lancet infectious disease series:

Combating Childhood Infections in LMICs: evaluating the contribution of Big Data

World Sepsis Day 2020 - webinar

Recording of our World Sepsis Day 2020 webinar.

Talking about Sepsis

This preview event took place on Wednesday 20 June 2018 in the 'Goldilocks Ward' of the new Sepsis Engagement Centre.

The event was very well attended with over 60 people from Cardiff University, Wales Gene Park, Cardiff & Vale UHB, Sêr Cymru, Welsh Government and The UK Sepsis Trust in attendance.

See more information about the Talking about Sepsis event.

View event Talking about Sepsis programme.

World Sepsis Day 2019

Sepsis: a spotlight on what can happen to mum and baby.

Sepsis is a life threatening condition from infection, that can affect anybody at any age.

However, it is more common in vulnerable populations such as the very young and the very old. What is often not recognised is the significance of sepsis in pregnancy.

At the event we told Amanda’s story about a mother and baby who were severely affected by sepsis.

This was a free event open to all and took place on Friday 13 September 2019 in the seminar room and Sepsis Engagement Centre at the Sir Geraint Evans Cardiovascular Research Building at the University Hospital of Wales.

Event feedback:

'Excellent microbiology talk - very good illustrative case with patient perspective'

'Excellent varied programme, particularly enjoyed the patient’s story'

'Wonderful clinical simulation'

'A privilege to join the discussion and an invaluable insight into the global challenges of tackling sepsis'

See more information about World Sepsis Day 2019.

View the World Sepsis Day 2019 programme.

Public engagement

Sepsis engagement centre.

We seek to promote interaction between patients, researchers, and clinical staff through the Sepsis Engagement Centre, physically located in the Sir Geraint Evans Cardiovascular Research Building, acting as an interaction and training hub. Planned audio-visual exhibitions include “The sepsis life cycle”, an exhibition of simulation wards with featured displays of neonatal intensive care unit (NICU), paediatric intensive care unit (PICU), adult intensive care unit (ICU), and an exhibit for scientific understanding of current and planned future medical tests and treatments for sepsis.

The Sepsis Engagement Centre aims to engage through outreach events and to promote patient and public involvement (PPI) for making a real difference in our research and the clinic for saving lives against sepsis.

Read more about the preview event that was held for the Sepsis Engagement Centre on 20 June 2018 .

Why the 'Golidlocks Ward' - The Goldilocks fairy tale

The Goldilocks fairy tale was first recorded in narrative form in 1837, in a collection of essays by Robert Southey titled “The Doctor.”

As in the house belonging to the three bears, the Goldilocks Ward has three beds, from our tiny neonatal cot to an adult hospital bed.  The distinct zones provide crucial opportunities for simulated training and research. They represent:

• Neonatal Intensive Care Unit (NICU)
• Paediatric Intensive Care Unit (PICU)
• Adult Intensive Care Unit (ICU)

The ‘Goldilocks principle’ means to strive for what is ‘just right’. Our interactive display explores the application of this principle to precision medicine and the antibiotic treatment of sepsis - getting just the right medicine to the right patient.

Sepsis is caused by an unbalanced immune reaction in our blood to fight infection. The main pathogens that can trigger sepsis range in size Fungal/Yeast, Bacterial, Viral.

A community action for getting involved to be involved in sepsis awareness and research

Central to helping us reach our goals are Lay Advisory groups for neonatal, paediatric, and adult sepsis, respectively. The role of our Lay Advisory groups is to help review research priorities, identify new lines of research, give input into research proposals (lay summaries in particular) and impact statements and website content, as well as contributes to the dissemination of research findings to relevant target groups.

Lay advisory involvement for project sepsis is underway with opportunities to join the pool of lay advisors in our community action against sepsis. We especially welcome those affected by sepsis either directly, as former patients, or indirectly as family members of former patients as well as those who wish to get involved out of general interest.

If you would like to find out more about patient and public engagement, please contact: [email protected]

Our lay advisory community

• Terence Canning (aSEP)
• Nicola Madoc-Jones (nSEP)
• David Madoc-Jones (nSEP)
• Holly Powell (nSEP)
• Tracey Laight (aSEP)
• Jacqueline Mason (aSEP)
• Alan Brown (aSEP)

Our funding

This project is part-funded by the European Regional Development Fund through the Welsh Government.

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School of Medicine

Project Sepsis involves studies of Neonatal, Paediatric, Maternal and Adult sepsis.

Diagram showing individual patients that either have blood culture positive sepsis (red dots) or are well babies (blue dots). The position indicates how the pattern of 10,000 most variable genes alters amongst the patients and if similar occupy a similar position, revealing a clear discrimination between healthy and sepsis babies.

Line graphs of pathway diagnostic markers of sepsis showing the values of gene expression activity associated with causal pathways of (a) innate immunity (in-born), (b) metabolism, (c) adaptive immunity (acquired) and (d) the integration of all three pathways in patients either having blood culture positive sepsis (red dots) or well babies (blue dots). A 100% accuracy in predicting sepsis is obtained when all three pathways are combined.

Project Sepsis team.

Medical professionals giving a demonstration in the sepsis engagement centre.

Project Sepsis team joined by fellow medical professionals in the engagement centre.

Research that matters

Our research makes a difference to people’s lives as we work across disciplines to tackle major challenges facing society, the economy and our environment.

Postgraduate research

Our research degrees give the opportunity to investigate a specific topic in depth among field-leading researchers.

Our research impact

Our research case studies highlight some of the areas where we deliver positive research impact.

A research project aiming to harness the immune system and its soft wiring to metabolism as a detector of infection.

Case-based learning: recognising sepsis

Sepsis can lead to organ failure and death. However, early diagnosis and recognition may help prevent these potentially fatal consequences.

JL / Science Photo Library / Shutterstock.com

Several personal stories of sepsis survivors and deaths from sepsis have been published in the media, highlighting the importance of sepsis as a major cause of preventable deaths in the UK. This article will provide an overview of sepsis with particular focus on the role of pharmacy professionals in recognition and referral.

Pathophysiology

Sepsis is characterised by a systemic inflammatory response to an invasive infection that has become unregulated [1] . White blood cells and pro-inflammatory cytokines are released causing widespread vasodilation and an increase in capillary permeability, resulting in the loss of fluid from circulation. This results in hypovolaemia and a fall in systemic vascular resistance, which in turn leads to a fall in blood pressure and a decrease in organ perfusion, culminating in tissue hypoxia and organ failure [1] .

There are around 250,000 cases of sepsis annually in the UK, 20% of which are fatal [1], [2] . The UK Sepsis Trust estimates that early diagnosis of sepsis and the application of evidence-based treatment could save 14,000 lives per year [2] . Therefore, the timely identification of sepsis can lead to rapid treatment and potential mortality reduction.

Initial recognition of sepsis relies on identifying symptoms, which presents challenges for healthcare professionals as the common symptoms are not specific to sepsis and could be caused by non-infective pathology (e.g. trauma, pancreatitis, burns ) [3] .

The inflammatory-response-induced hypovolaemia affects the brain and can cause confusion, slurred speech and loss of consciousness. Similarly, as the kidneys are affected, there is a reduction in glomerular filtration resulting in a drop in urine output and development of acute kidney injury [1] , [3] .

Gas exchange across the alveoli is compromised as fluid and proteins leak into the lungs, causing a drop in systemic oxygen saturation and a rise in carbon dioxide levels. The body attempts to compensate by increasing its respiratory rate, but the problem is ultimately compounded as the drop in organ perfusion affects the lungs, meaning that even if oxygen-rich air is present, there is little blood flow with which gas exchange can take place [1] , [3] .

Initially, the heart rate increases in an attempt to compensate for the drop in blood pressure. However, the reduction in circulating volume and the fall in systemic vascular resistance ultimately undermine this action. This is because a reduction in venous return prevents the ventricles from properly filling before they contract, reducing the cardiac output [1] .

The typical signs and symptoms of sepsis may vary across different age groups, be general or may not all be present. Examples of moderate- and high-risk symptoms include:

• Reduced urine output (e.g. dry nappies in babies and toddlers);
• Feeling cold with shivering or chills;
• Rapid breathing (increased resting breaths per minute);
• Rapid heart rate (increased resting heart rate per minute);
• Mottled (see Photoguide A) or ashen appearance;
• Cyanosis (blue tint) of skin, lips or tongue (see Photoguide B);
• Non-blanching rash (see Photoguide C) [1] , [4] , [5] .

Additional signs in babies and young children (aged under five years)

• Not responding normally to social cues (e.g. does not smile);
• Visibly unwell (e.g. floppy or overly passive);
• Wakes only with prolonged stimulation or, if roused, does not stay awake;
• Weak high-pitched or continuous cry;
• Parent or carer is concerned that the child is behaving differently from normal;
• Has a seizure or convulsion;
• Pallor of the skin, lips or tongue;
• Cold extremities, but head and torso may be hot to the touch;
• Change in temperature (e.g. red flag temperatures are over 38 o C in those aged under 3 months, 39 o C in those aged 3–6 months and less than 36 o C for any age) [1] , [4] , [5] .

Additional signs that can affect patients aged over five years

• Evidence of new-onset confusion (history may be from a parent, carer, relative or friend);
• Slurred speech;
• Signs of potential infection (e.g. redness, swelling or discharge at surgical site, breakdown of the wound);
• Tympanic temperature less than 36 o C;
• New onset arrhythmia [1] , [4] , [5] .

If sepsis is suspected, the patient should be immediately referred for emergency medical assessment. 

Photoguide: symptoms of sepsis

Source: Science Photo Library / Shutterstock.com

At-risk groups

Sepsis can affect anyone, but there are some patient groups that should be considered to be more susceptible to the development of sepsis, including:

• Very young children (aged under 1 year);
• Frail or older people (aged over 75 years);
• Immunocompromised people (e.g. those being treated for cancer with or without chemotherapy, post-splenectomy, taking long-term steroids or other immunosuppressant drugs);
• People who have had surgery or other invasive procedures in the past six weeks;
• People with any breach of skin integrity (e.g. cuts, burns, blisters or skin infections);
• People who misuse drugs intravenously;
• People with indwelling lines or catheters;
• Pregnant women;
• Women who have given birth or who have had a termination of pregnancy or miscarriage in the past six weeks [4] .

Understanding the patient risk factors may help improve timely diagnosis of suspected sepsis.

Sepsis can occur in response to a wide range of infections, but is most commonly associated with bacterial infection of the lungs, urinary tract, abdomen, central nervous system, or skin and soft tissues [1] . It is primarily diagnosed by a clinical assessment. Any number or combination of signs and symptoms may be present on diagnosis.

The National Institute of Health and Care Excellence (NICE) and the UK Sepsis Trust have published risk stratification tools to facilitate appropriate recognition of sepsis and the level of risk to the patient. Most NHS organisations use these tools or a locally approved variation of them [1] , [4] . These tools cater to a wide range of patients of different ages and the recommended action differs depending on whether patients’ symptoms are recognised in the primary or secondary care setting.

Patients who meet the high-risk criteria (see Box for the criteria for children aged under five years) should be sent urgently for emergency care (at a setting with resuscitation facilities). These patients should receive intravenous antibiotics with an appropriate level of cover within one hour of recognition of sepsis, along with other treatments and investigations [1] , [4] .

Box: high-risk criteria for children aged under five years outside of the hospital setting

• No response to social cues;
• Appears ill to a healthcare professional;
• Does not wake, or if roused, does not stay awake;
• Weak high-pitched or continuous cry.
• Aged under one year: 160 beats per minute or more;
• Aged one to two years: 150 beats per minute or more;
• Aged three to four years: 140 beats per minute or more;
• Heart rate less than 60 beats per minute at any age.

Respiratory rate

• Aged under one year: 60 breaths per minute or more;
• Aged one to two years: 50 breaths per minute or more;
• Aged three to four years: 40 breaths per minute or more;
• Oxygen saturation of less than 90% in air or increased oxygen requirement over baseline.

Temperature

• Aged under three months: 38°C or more;
• Any age: less than 36°C.

To see examples of mottled skin or ashen appearance, non-blanching rash of the skin, and cyanosis of the skin, lips or tongue, see the Photoguide.

Source: National Institute for Health and Care Excellence [8]

Initial blood tests should be requested to aid diagnosis and further inform on the likelihood of infection and prognosis. These should include:

• C-reactive protein — to detect inflammatory response;
• Full blood count — to detect immune response;
• Lactate — to detect tissue hypoxia.

Other investigations, such as a chest X-ray or lumbar puncture, may also be indicated depending on the likely focus of the suspected infection.

Point-of-care testing and future diagnostics

In the future, point-of-care testing facilities for key biomarkers may have a greater role in both primary care and hospital emergency departments, aiding healthcare professionals in diagnosing infection and sepsis. Recently published research into the use of sensor technologies designed to rapidly report on raised levels of biomarkers closely associated with sepsis (notably interleukin-6) may have the potential to aid sepsis diagnosis in the future [6] , [7] .

Case studies

Case study 1: a 12-month-old baby with suspected sepsis.

A mother brings her 12-month-old daughter Alice* into the pharmacy and asks to speak to the pharmacist. The mother clearly appears concerned and expresses that Alice seems very poorly and is not her usual self.

Consultation

The mother explains that her daughter attended nursery today and the nursery staff phoned in the afternoon to report that Alice was not feeling well. As she had a temperature of 39 o C, they administered a dose of paracetamol. The nursery staff also said that Alice had not been eating or drinking well and her nappies were dry all day.

Alice takes no regular medicine and has no ongoing health problems. She seems withdrawn and is not smiling or engaging with anyone, which the mother insists is unusual behaviour.

When assessing the patient, Alice’s hands feel cold despite her body and head feeling hot. During the interaction with Alice, she is noticeably very passive and inactive, and seems floppy in her mother’s arms. Alice does not appear to have a rash, though her skin appears pale.

Alice’s breathing appears very rapid.

Information given in the consultation suggests that Alice may have sepsis. Use the  National Institute for Health and Care Excellence ‘Sepsis risk stratification tool’ for children aged under five years out of hospital and compare it to the information obtained during the consultation [8] . By doing so, it is apparent that the following moderate-to-high risk criteria were demonstrated by the patient:

• Behaviour: parent or carer concern that the child is behaving differently than usual; not responding normally to social cues; no smile; and decreased activity;
• Cold hands or feet;
• Reduced urine output;
• Between 40 and 49 breaths per minute (normal resting respiratory rate for a 12-month-old is typically 20–40 breaths per minute);
• Pallor of skin, lips or tongue.

Although her temperature was high (39 o C), this would only be a moderate-risk criterion if Alice was aged between 3–6 months of age outside the hospital setting.

Advice and recommendations

Alice’s symptoms clearly indicate moderate-to-high risk of sepsis. According to the risk stratification tool, Alice should be referred either for a definitive diagnosis for treatment outside the hospital (i.e. to the patient’s GP), or to hospital for further review.

Considering the risk of sepsis and the importance of timely management, referral to hospital is the best choice for this patient. Calmly and clearly explain to the mother that Alice may have a serious infection and that the best course is for her to go to the hospital immediately.

Case study 2: an 11-year-old child with a viral infection

An 11-year-old boy called Liam* is brought into the pharmacy by his parents. They explain that he has not been feeling well for the past few days. The parents want to know if Liam’s symptoms can be treated with an over-the-counter (OTC) product or whether they should take him to the GP.

Liam has been unwell for the past three or four days and his condition does not seem to be improving. He has not yet taken any medicine for this illness. His temperature was 37.8 o C when most recently checked using an ear thermometer at home.

Liam says that he has a sore throat, a cough and a blocked nose. Liam describes the severity of his throat pain as three out of ten. Liam has been eating and drinking normally, has no long-term medical conditions and takes no regular medicine.

Liam and his parents agree that his behaviour and function are normal and he appears alert and coherent through the consultation. Liam’s breathing rate does not appear to be raised and his skin and lips appear normal, with no signs of a rash.

Liam may have an infection, which is likely to be viral, but does not require medical attention at present. However, to rule out sepsis, use the  National Institute for Health and Care Excellence ‘Sepsis risk stratification tool’ for children aged 5–11 years out of hospital and compare this to the information obtained during the consultation [8] . By doing so, it is apparent that no moderate-to-high risk criteria were demonstrated by the patient.

Liam can be treated with OTC analgesics to alleviate his throat pain and his raised temperature. Liam’s parents should ensure he is taking plenty of fluids and continue to monitor his temperature. If they become concerned about his condition, his behaviour or general functional ability, they should return to or call the pharmacy. Particular symptoms you advise them to look out for include development of a rash, if his skin becomes pale or mottled, his urine output drops, his breathing rate increases, or any general concern that mental state or activity is not normal.

Case study 3: an adult with red flag sepsis

Rahul*, a 28-year-old man, comes into the pharmacy and asks to see the pharmacist as he has begun to feel very unwell.

Rahul works as a driver, and he fell and scraped his leg while getting out of his van the previous day. Rahul explains that at the time he did not think much about the cut, so he did not clean or dress the wound and has not yet taken any medicine for it. Although the wound began to swell and weep overnight, Rahul went into work this morning, but left when he suddenly started to feel seriously unwell — around an hour ago.

Rahul says the wound now looks much worse than it previously did. On examination you find the wound is very red and swollen, the tissue around the wound is blistering and weeping, and there are red track marks extending further up Rahul’s leg. It is clear that this wound is infected.

Rahul uses inhalers for mild asthma, but otherwise takes no regular medicine.

Rahul says he is feeling hot and sluggish, and is clearly struggling to maintain his train of thought. His condition appears to be worsening by the minute. He needs to be referred for further help, but more information is required to decide whether he is referred to his GP or to a hospital emergency department. 

Rahul’s temperature is 35.8 o C. His breathing appears to be rapid. His blood pressure is 92/58mmHg and his heart rate is 140 beats per minute. Rahul does not appear to have a skin rash, although his lips seem to have a blue tint.

Rahul is likely to have a serious infection, which requires urgent attention. Use the National Institute for Health and Care Excellence ‘Sepsis risk stratification tool’ for people aged 18 years and over outside of the hospital setting and compare this to the information obtained during the consultation [8] . The patient has moderate- to high-risk criteria, such as tympanic temperature less than 36 o C and signs of potential infection. He also has several high-risk criteria that require urgent referral to emergency care:

• Altered behaviour or mental state;
• Respiratory rate over 25 breaths per minute;
• Heart rate more than 130 beats per minute;
• Cyanosis of skin, lips or tongue.

Tell Rahul that it is likely that he has a serious infection, and ask him to sit and wait in the pharmacy while an ambulance is called. It is not safe for him to drive to hospital. Share his information with the 999 operator and make another note of the details gathered during the consultation to hand over to the ambulance team upon arrival.

*All cases are fictional

Useful additional resources

• The UK Sepsis Trust. The Sepsis Manual. 2017–2018: Available at:  https://sepsistrust.org/wp-content/uploads/2018/06/Sepsis_Manual_2017_web_download.pdf
• National Institute for Health and Care Excellence. Sepsis: risk stratification tools. Available at:  https://www.nice.org.uk/guidance/ng51/resources/algorithms-and-risk-stratification-tables-compiled-version-2551488301
• For patients who are interested in finding out more about sepsis you can direct them to the NHS website. Available at:  https://www.nhs.uk/conditions/sepsis/

[1] The UK Sepsis Trust. The Sepsis Manual. 2017–2018. 2017. Available at: https://sepsistrust.org/wp-content/uploads/2018/06/Sepsis_Manual_2017_web_download.pdf (accessed October 2019)

[2] The UK Sepsis Trust. Professional Resources. Available at: https://sepsistrust.org/professional-resources/ (accessed October 2019)

[3] Gotts JE & Matthay MA. Sepsis: pathophysiology and clinical management. BMJ 2016;353:i1585.  doi: 10.1136/bmj.i1585

[4] National Institute for Health and Care Excellence. Sepsis: recognition, diagnosis and early management. NICE guideline [NG51]. 2016. Available at: https://www.nice.org.uk/Guidance/NG51 (accessed October 2019)

[5] National Health Service: Overview — Sepsis. 2019. Available at: https://www.nhs.uk/conditions/sepsis/ (accessed October 2019)

[6] Russell C, Ward AC, Vezza V et al . Development of a needle shaped microelectrode for electrochemical detection of the sepsis biomarker interleukin-6 (IL-6) in real time. Biosens Bioelectron 2019;126:806–814. doi: 10.1016/j.bios.2018.11.053

[7] Dolin H, Papadimos T, Stepkowski S et al. A novel combination of biomarkers to herald the onset of sepsis prior to the manifestation of symptoms. Shock 2018;49(4):364–370. doi: 10.1097/SHK.0000000000001010

[8] National Institute for Health and Care Excellence. Sepsis: Risk stratification tools. 2017. Available at: https://www.nice.org.uk/guidance/ng51/resources/algorithms-and-risk-stratification-tables-compiled-version-2551488301 (accessed October 2019)

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Amanda Harvey, Clinical Skills Facilitator and Rebecca McLaughlin, Staff Nurse ITU, University Hospitals of Morecambe Bay NHS Foundation Trust

Amanda and Rebecca led a project called Think Sepsis, Save Lives.

Sepsis affects 150,000 people and leads to around 44,000 deaths per year in the UK alone. Amanda and Rebecca's mission was to increase understanding and recognition of sepsis among staff and patients, and reduce harm.

The project involved a large scale training program for clinical staff, including the introduction of ward based champions. The team developed resources such as screening tools, posters and pocket sized reference cards.

Sepsis training was also introduced into other existing training courses with collaborative working taking place between Practice Educators. Public and staff awareness events were also held.

At the end of the project the team had trained around 1,200 clinical staff in the recognition and management of sepsis. Sepsis screening in emergency admissions had increased from 22% in March 2015 to 56% in March 2016 and administration of antibiotics within the hour, as per Sepsis Six recommendation had increased from 61% in July 2015 to 72% in March 2016.

Following the Think Sepsis, Save Lives Campaign University Hospitals of Morecambe Bay NHS Foundation Trust has continued to make improvements in sepsis care. As of March 2018:

• 100% of both emergency admissions and inpatients were screened for sepsis
• 91% of emergency admissions and 94% of inpatients received antibiotics within the hour

The Think Sepsis, Save Lives scheme provided a vehicle to initiate change, and the improvements have been sustained long after its completion, leading to significant improvements in patient safety.

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Association of Annual Intensive Care Unit Sepsis Caseload With Hospital Mortality From Sepsis in the United Kingdom, 2010-2016

Ritesh maharaj.

1 Department of Health Policy, London School of Economics and Political Science, London, UK

2 Department of Critical Care, Kings College Hospital NHS Foundation Trust, London, UK

Alistair McGuire

Andrew street.

Accepted for Publication: April 27, 2021.

Published: June 29, 2021. doi:10.1001/jamanetworkopen.2021.15305

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2021 Maharaj R et al. JAMA Network Open .

Author Contributions: Dr Maharaj had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Maharaj, Street.

Drafting of the manuscript: Maharaj, Street.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Administrative, technical, or material support: McGuire.

Supervision: Street.

Conflict of Interest Disclosures: None reported.

Associated Data

eFigure 1. Study patient flow

eFigure 2. Violin plot of annual ICU sepsis volume between 2010 and 2016

eTable 1. Characteristics of patients admitted to the ICU with between 2010 and 2016 and quantiles of annual ICU case load of sepsis

eTable 2. ICU characteristics between 2010 and 2016

eFigure 3. Results of the regression analysis with volume as quartiles

eTable 3. Testing the statistical significance between models of increasing complexity with volume defined as a restricted cubic spline

eFigure 4. Variation within ICUs across years empirical Bayes predication

eFigure 5. Subgroups analysis: Adjusted probability of mortality

eTable 4. Comparisons of model fit for fractional polynomial

eFigure 6. Functional form of fractional polynomial

eTable 5. A comparison of the information criteria for the linear, fractional polynomial and restricted cubic spline models

eFigure 7. Value of the joint minimum strength of association that an unmeasured confounder must have with both an increase in ICU sepsis volume and acute hospital mortality to explain away the volume outcome relationship, expressed as a risk ratio

eTable 6. Within and between cluster effects of ICU volume test for exogeneity

eReferences

This cohort study assesses the association between the annual volume of patients with sepsis treated in intensive care units of UK hospitals and hospital mortality from sepsis between 2010 and 2016.

Is there an association between the annual volume of sepsis cases in an intensive care unit (ICU) and hospital mortality from sepsis?

In this cohort study of 273 001 patients with sepsis at 231 ICUs in the UK, a higher annual sepsis case volume in the ICU was associated with significantly lower hospital mortality, and this association had no significant interaction with illness severity. A lower volume threshold of 215 treated patients was identified, above which hospital mortality decreased significantly.

The findings suggest that patients with sepsis in the UK have higher odds of survival if treated in an ICU with a higher sepsis case volume.

Sepsis is associated with a high burden of inpatient mortality. Treatment in intensive care units (ICUs) that have more experience treating patients with sepsis may be associated with lower mortality.

To assess the association between the volume of patients with sepsis receiving care in an ICU and hospital mortality from sepsis in the UK.

Design, Setting, and Participants

This retrospective cohort study used data from adult patients with sepsis from 231 UK ICUs between 2010 and 2016. Demographic and clinical data were extracted from the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme database. Data were analyzed from January 1, 2010, to December 31, 2016.

Annual sepsis case volume in an ICU in the year of a patient’s admission.

Main Outcomes and Measures

Hospital mortality after ICU admission for sepsis assessed using a mixed-effects logistic model in a 3-level hierarchical structure based on the number of individual patients nested in years nested within ICUs.

Among 273 001 patients included in the analysis, the median age was 66 years (interquartile range, 53-76 years), 148 149 (54.3%) were male, and 248 275 (91.0%) were White. The mean ICNARC-2018 illness severity score was 21.0 (95% CI, 20.9-21.0). Septic shock accounted for 19.3% of patient admissions, and 54.3% of patients required mechanical ventilation. The median annual sepsis volume per ICU was 242 cases (interquartile range, 177-334 cases). The study identified a significant association between the volume of sepsis cases in the ICU and mortality from sepsis; in the logistic regression model, hospital mortality was significantly lower among patients admitted to ICUs in the highest quartile of sepsis volume compared with the lowest quartile (odds ratio [OR], 0.89; 95% CI, 0.82-0.96; P  = .002). With volume modeled as a restricted cubic spline, treatment in a larger ICU was associated with lower hospital mortality. A lower annual volume threshold of 215 patients above which hospital mortality decreased significantly was found; 38.8% of patients were treated in ICUs below this threshold volume. There was no significant interaction between ICU volume and severity of illness as described by the ICNARC-2018 score (β [SE], –0.00014 [0.00024]; P  = .57).

Conclusions and Relevance

The findings suggest that patients with sepsis in the UK have higher odds of survival if they are treated in an ICU with a larger sepsis case volume. The benefit of a high sepsis case volume was not associated with the severity of the sepsis episode.

Introduction

Sepsis is a dysregulated host response to infection that results in organ dysfunction. 1 It is among the leading causes of death worldwide, and the global burden of sepsis is expected to increase as populations age. 2 The World Health Assembly has urged member states and other stakeholders to strengthen efforts to prevent, diagnose, and treat sepsis. 3 Patients with sepsis require high-cost interventions in intensive care units (ICUs), where even with prompt treatment, they have a high probability of death. 2 One strategy to reduce mortality might be to treat patients with sepsis in larger, high-volume ICUs.

Since a seminal report by Luft et al in 1979, 4 there has been increasing evidence that patients receiving treatment for complex conditions have lower mortality when treated in institutions with a high-volume caseload compared with institutions with a low-volume caseload. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 Other major benefits are the potential for lower costs by economies of scale and more efficient use of staff and other resources. 12 The main concerns are the potential for fragmentation of care, the need to transport patients away from their local hospital, and the possibility that high-volume centers will be overwhelmed. 13

Sepsis, although common and clinically identifiable, has not attracted much attention in the literature assessing the association of case volume with outcomes. 1 , 14 Sepsis requires time-critical interventions provided almost exclusively within the ICU, allowing assessment of the direct association of outcomes with ICU treatment. Thus, we evaluated the association between annual sepsis case volume in an ICU and hospital mortality among patients with sepsis in the UK. We chose mortality as the outcome because sepsis is associated with significant mortality, 15 and this outcome is not subject to manipulation.

In this cohort study, we analyzed data from the Case Mix Programme database, a national clinical database of all adult patients admitted to ICUs in England, Wales, and Northern Ireland that is coordinated by the Intensive Care National Audit & Research Centre (ICNARC). Details of the validation of the Case Mix Programme database were published previously. 16 , 17 , 18 , 19 , 20 Approval for the use of data from the Case Mix Programme was obtained under §251 of the National Health Service Act 2006. The London School of Economics waived the requirement for approval and informed consent because this research involved secondary analysis of an established data set of anonymized data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. 21

Patient Selection

All admissions of adults with sepsis to 231 general ICUs in England, Wales and Northern Ireland between January 1, 2010, and December 31, 2016, were included. Sepsis cases were identified using the third international consensus definitions for sepsis and septic shock (Sepsis-3). 1 We considered the index critical care admission for sepsis as an admission for an infection with a sequential organ failure score of 2 or higher. Septic shock was defined as infection with a Sequential Organ Failure Assessment score of 2 or higher with a cardiovascular component or with a serum lactate concentration greater than 18 mg/dL, in accordance with the Sepsis-3 definition. 1 Patients younger than 16 years, patients for whom all physiological data were missing, and patients who stayed in the ICU for less than 8 hours were excluded.

The exposure was defined as the annual sepsis case volume in an ICU in the year of a patient’s admission; for example, if a patient was admitted to an ICU in 2010, we defined exposure as the sepsis case volume in that ICU in 2010. In the initial data analysis, we followed the common approach of categorizing ICU volumes into quartiles, which we justified given that we were analyzing the complete set of general ICUs in England, Wales, and Northern Ireland. Our preferred approach was to specify volume as a continuous variable and used restricted cubic splines to identify the best-fitting model.

Study Outcome

The primary outcome was death before discharge from an acute care hospital. Patients who were transferred between ICUs were excluded from the analysis of mortality but included in the estimation of ICU volumes. This was done to avoid confounding results with outcomes from different ICUs. For patients who were readmitted to the ICU, only the first admission was included in the mortality analysis.

Statistical Analysis

Data were analyzed from January 1, 2010, to December 31, 2016. The risk-adjusted association between ICU volume and acute care hospital mortality was assessed using a mixed-effects logistic model in a 3-level hierarchical structure based on the number of individual patients nested in years nested within ICUs. This mixed-effects approach was used to evaluate the association between the volume of sepsis cases in an ICU and mortality from sepsis while giving adequate control for the within-ICU variation over time. Control variables included in the model were age, sex (with female as the reference), prehospital dependence (with no dependence as the reference), race/ethnicity (with White as the reference), comorbidities (with severe respiratory disease, severe cardiac disease, end-stage kidney disease, severe liver disease, metastatic disease, hematological malignancy, and compromised immune system as the reference), socioeconomic deprivation as measured by the Index of Multiple Deprivation, severity of illness as measured by the ICNARC-2018 score, 22 , 23 annual bed occupancy rate, and academic affiliation (with nonuniversity as the reference). Race/ethnicity was defined using the UK Census recommendations of categorization. 24 Race/ethnicity was included as a control variable because of the association with mortality from sepsis. 25 , 26 , 27 Full details are provided in the eAppendix in the Supplement .

The annual ICU sepsis case volume was initially analyzed as a categorical variable, as in earlier studies. 28 Categorization is a popular method for studies on case volume and outcomes but has disadvantages. The categories are determined by the distribution of the data; thus, the cutoff points are arbitrary and study specific, limiting generalization. There is also substantial loss of information through categorization, with all ICUs in the same category assumed to have the same mortality risk.

Our subsequent data analysis therefore defined volume as a continuous variable, and we specified restricted cubic splines to allow for assessment of the nonlinear association between case volume and mortality. In making the model more flexible, potential overfitting was avoided, whereas the interpretability of the modeled association was retained. Restricted cubic splines can identify local features and provide stable estimates at the tails of data, making the spline model reliable in identifying a local marginal treatment effect. We fitted models with 3, 4, 5, and 6 knots and used information criteria and likelihood ratio tests to select the model with 3 knots as the most parsimonious. 29 We used a Wald test to assess the overall association between sepsis case volume and mortality. We specified values of ICU volume at midpoints on the knots to provide a comparison with the quartile model. 30 Details, including various specification tests, are given in the eAppendix in the Supplement . Significance was defined as P  < .05 using a 2-tailed test. Data analysis was performed using Stata, version 16.0 (StataCorp LLC).

We used the 3-level hierarchical logistic regression model to account for the clustering of patients within ICUs across years. This approach also estimated random intercepts for each ICU, which were interpreted as the latent ICU-level variation. 31 Details are included in the eAppendix in the Supplement . We evaluated the significance of the between-ICU variation using a median odds ratio (OR). 32

Subgroup Analysis

We hypothesized that sicker patients would have a lower mortality risk if treated in a high-volume ICU vs a low-volume ICU. To assess this, we performed a test of the interaction between ICU volume and illness severity using the mortality risk estimated using the ICNARC-2018 score. We examined sensitivity in this subgroup analysis by altering the definition of more severely ill. We subsequently defined sicker patients admitted to ICUs as those with septic shock, those with an expected mortality rate greater than 30% as estimated by the ICNARC model, or those who received mechanical ventilation or kidney replacement therapy within 20 hours of ICU admission. Second, we analyzed nonsurgical patients with sepsis to ensure that the observed outcome was not influenced by inclusion of surgical patients with sepsis.

Sensitivity Analysis

We used fractional polynomials as an alternate specification of volume as a continuous variable to test the sensitivity of the results to the specification of the association between case volume and outcome. 29 Fractional polynomials are global functions and may obscure local features, particularly at the tails of the data distribution, and may therefore be less useful than cubic splines in identifying a threshold volume, particularly at low volumes. 33

We then performed a quantitative bias assessment to assess the influence of unmeasured covariates 34 , 35 using E-values. E-values measure the minimum association that an unmeasured covariate would require with both ICU volume and mortality, conditional on the measured covariates, to explain the empirically determined association between case volume and outcome. 35

In addition, we checked that volume was exogenous. In this study’s model, exogeneity required that ICU volume was not associated with the ICU-level random effect. 36 Details are provided in the eAppendix in the Supplement .

Descriptive Statistics

Of the 305 748 ICU admission episodes (which included readmissions and transfers) meeting the Sepsis-3 criteria between 2010 and 2016, 32 747 (10.7%) were excluded from the mortality analysis. This included 19 809 patients who were readmitted, 12 296 patients transferred between ICUs, and 642 patients who were readmitted and transferred between ICUs. Descriptive statistics for the sample of 273 001 patients with sepsis treated within general ICUs from 2010 to 2016 are shown in Table 1 and eTable 1 in the Supplement ; patient flow is shown in eFigure 1 in the Supplement . The median age of the patients was 66 years (interquartile range [IQR], 53-76 years); 148 149 (54.2%) were male, and 248 275 (91.0%) were White. The mean ICNARC-2018 score was 21.0 (95% CI, 20.9-21.0) Most of the patients (80.1%) had no severe medical comorbidity. Of all included patients, 1.8% were recorded as having severe cardiac disease, 4.6% as having severe respiratory disease, 1.9% as having end-stage kidney disease, and 2.2% as having liver disease; 8.8% were recorded as immunocompromised. The mean ICNARC-2018–estimated mortality rate was 29.7% (95% CI, 29.6%-29.8%). Mechanical ventilation was used for 53.1% of patients, 19.9% had a diagnosis of septic shock, and 8.8% had received kidney replacement therapy within 24 hours of ICU admission.

Abbreviations: APACHE II, Acute Physiologic Assessment and Chronic Health Evaluation II; ESKD, end-stage kidney disease; ICNARC, Intensive Care National Audit & Research Centre; ICU, intensive care unit; IMD, Index of Multiple Deprivation; IQR, interquartile range.

The unadjusted hospital mortality rate was 31.9% (95% CI, 31.8%-32.1%). Hospital mortality was 33.3% in the lowest volume quartile compared with 30.7% in the highest quartile ( Table 1 ).

Of the 231 ICUs, 122 (52.8%) were in non–university hospitals, 39 (16.9%) were university affiliated, and 70 (30.3%) were university based. The median number of ICU beds was 8 (IQR, 6-10) in the lowest quartile of ICU volume compared with 23 (IQR, 18-28) in the highest quartile ( Table 2 and eTable 2 and eFigure 2 in the Supplement ).

Abbreviations: ICU, intensive care unit; IQR, interquartile range.

Regression Analysis

The logistic regression model revealed a statistically significant reduction in hospital mortality among patients admitted to ICUs in the highest quartile of sepsis volume compared with those admitted to ICUs in the lowest quartile (OR, 0.89; 95% CI, 0.82-0.96; P  = .002) ( Table 3 , Figure 1 , and eFigure 3 in the Supplement ).

Abbreviations: NA, not applicable; OR, odds ratio.

A, Markers represent adjusted probabilities and whiskers indicate 95% CIs. B, Shaded area indicates 95% CI. C, Shaded area indicates 95% CI; dashed vertical line indicates the threshold at which an increase in volume resulted in a significant reduction in estimated mortality.

With volume modeled as a restricted cubic spline, greater ICU volume was associated with lower hospital mortality ( Figure 1 and eTable 3 in the Supplement ). The marginal treatment effect refers to the estimated change in mortality per unit change in ICU volume and varied with the point of estimation in nonlinear models. The restricted cubic spline specification identified a lower threshold of 215 patients with sepsis treated per year, above which greater sepsis case volume in the ICU was associated with lower mortality ( Figure 1 ). Above this volume threshold, there was a significant reduction in mortality ( Figure 1 and Table 3 ). Altogether, 38.8% of patients with sepsis were treated in ICUs below this threshold value. We could not identify an upper threshold value.

The between-ICU practice variation was derived from the mixed-effects model using estimated random intercepts as a measure of latent quality. The median OR for hospital mortality was 1.27 (95% CI, 1.23-1.30), suggesting significant unexplained between-ICU practice variation. The variance within the same ICU across the study period did not change significantly, suggesting that an individual ICU’s performance in terms of mortality was stable over time (eFigure 4 in the Supplement ).

Subgroup Analyses

There was no significant interaction between ICU volume and severity of illness as described by the ICNARC-2018 score (β [SE], –0.00014 [0.00024]; P  = .57). In addition, subgroup analyses of patients defined as severely ill also did not identify a lower sepsis case volume threshold for mortality (subgroup receiving mechanical ventilation: β [SE], –0.00056 [0.00019]; P  = .003; subgroup with >30% predicted mortality: β [SE], –0.00032 [0.00019]; P  = .10; subgroup receiving kidney replacement therapy <24 hours after ICU admission: β [SE], 0.00023 [0.00035]; P  = .51; and subgroup with septic shock: β [SE], –0.00051 [0.00026]; P  = .052) ( Figure 2 ). The association between case volume and mortality found in the subgroup of nonsurgical patients with sepsis was similar to that in the entire cohort (β [SE], 0.00053 [0.00018]; P  = .002) ( Figure 2 and eFigure 5 in the Supplement ).

Shaded areas indicate 95% CIs. ICNARC, Intensive Care National Audit & Research Centre.

The association between case volume and mortality remained statistically significant in the fractional polynomial model (eFigure 6 and eTables 4 and 5 in the Supplement ). The quantitative bias analysis returned an E-value of 1.31 (lower bound of 95% CI, 1.17) (eFigure 7 and eAppendix in the Supplement ). The lack of statistical significance in the between- and within-cluster effects for ICU volume indicated a lack of correlation in the ICU volume and the ICU random effect, in support of the assumption that ICU sepsis volume is exogenous (eTable 6 in the Supplement ).

In this cohort study, we found a significant association between the sepsis case volume in an ICU and hospital mortality from sepsis, and the association was consistent across the categorical and nonlinear specifications of ICU volume. The sepsis volumes included in this study exceeded the spectrum of volumes described in other published studies, 37 , 38 thereby improving the power to detect even a small association between case volume and mortality.

The study also identified a lower volume threshold of 215 patients treated per year, above which there was a statistically significant reduction in mortality. This threshold was estimated based on our preferred empirical specification using a 3-knot restricted cubic spline regression, which also controlled for a rich set of covariates to model the association between the case volume and mortality. There was no significant interaction between case volume and severity of illness. The study found that significant ICU practice variation was not explained by patient or hospital characteristics, implying that sample selection was not distorting the associations described. The within-ICU variation remained unchanged across years, suggesting that higher-performing ICUs maintained good performance over time.

The study’s findings are based on a large population of ICUs observed over time. A recent meta-analysis 28 of smaller observational studies found an overall positive association of outcome with ICU volume; however, there was significant heterogeneity. Some previous studies 39 , 40 that did not account for the clustered nature of the data revealed upwardly biased estimates of the association between case volume and outcome. The hierarchical structure of the current data analysis may account for the more modest association found in this study compared with other published studies. 28

Prior studies 28 , 37 , 41 , 42 of the association between case volume and outcomes among patients with sepsis have shown conflicting results. The literature is subject to limitations. 37 , 41 , 43 , 44 , 45 First, many of the studies 38 , 46 , 47 , 48 , 49 , 50 of case volume and outcomes among patients with sepsis were undertaken in the US, where there is a complex system of health care funding and where the observed benefits attributed to volume may to some extent reflect unmeasured disparities in access to care as well as socioeconomic disparities. Studies undertaken in countries such as Canada, Finland, or the UK, where there are single-payer, publicly funded health care systems, have not shown a consistent association between the volume of sepsis cases and outcomes. 37 , 45 , 51 Second, in comparisons between high- and low-volume specialist and nonspecialist services, some of the observed benefits of high case volume may in fact be a result of specialization.

Third, a major limitation of the existing literature on the association between ICU sepsis case volume and outcomes is the lack of a criterion standard for defining volume. 28 Examining quartiles does not improve the general understanding of the association between sepsis case volume in the ICU and outcomes because ICUs considered to be high volume in 1 study may be within a lower volume quartile in another study because the quartiles are specific to each data set. In this study, we used restricted cubic splines that allowed flexibility in describing the functional form of volume in regression models. In using the full range of data, these methods provided a more accurate description of the association between volume and mortality, with the additional ability to suggest optimal volume thresholds. Fourth, many studies included a small number of ICUs with a narrow spectrum of volumes, leaving them underpowered to detect a small but statistically and clinically meaningful association between case volume and outcome.

In addition, most studies use secondary administrative data collected for other uses. Such data have inherent limitations in both the identification of sepsis and the characteristics of patients and ICUs. This study used a large clinical database of patients with sepsis admitted to all general ICUs in the UK, allowing us to perform detailed risk adjustment and identify ICU-specific characteristics.

In the UK, ICUs are unable to make a risk-based selection of patients with sepsis who are at low risk of mortality because sepsis is an emergency condition and patients are taken to the nearest hospital, often by the ambulance service. The empirical findings of this study suggest treatment benefits could be made through a concentration of ICU facilities, similar to the successful policy adopted by the National Health Service in some areas with respect to the treatment of stroke. 52

Strengths and Limitations

This study has strengths. In terms of completeness, coverage, and representativeness of the data, this was one of the largest studies to examine the association between ICU volume and outcomes for patients with sepsis. By including all general ICUs in England, Wales, and Northern Ireland, the study assessed the entire adult population treated for sepsis in these countries during the study period. 16 This study used a granular clinical database with a standardized data collection process and a validated risk adjustment model developed for UK ICUs, and it used the international consensus Sepsis-3 definition to identify patients with sepsis. 1 , 16 , 22 , 38 The potential for selection bias was limited by using a cohort of patients with sepsis treated in publicly funded general ICUs within the UK National Health Service, which covers the whole population.

This study also has limitations. We used observational data that may have been subject to unmeasured confounding. We evaluated the potential for unmeasured confounding using E-values, 35 which resulted in a threshold risk ratio of 1.17. Although the E-value is modest, we believe that, given the detailed clinical data recorded in the Case Mix Programme database, substantial unmeasured confounding was improbable. If an omitted variable was associated with an included covariate, the omitted variable would not result in substantial bias. The E-value assumes that the distribution of unmeasured confounders is as unfavorable as possible and represents the most conservative scenario. 35

As is typical in the literature on case volume and outcome, we used the contemporaneous ICU volume as the exposure. This did not distinguish between the static scale effects of volume and the cumulative learning-by-doing effects. In addition, the data set did not have details on processes of care specific to sepsis, such as timing of the first dose of antibiotics. We were therefore unable to establish the underlying mechanism of association of sepsis case volume in the ICU with mortality from sepsis.

Conclusions

In this cohort study, sepsis case volume in an ICU was significantly associated with hospital mortality from sepsis, and a volume threshold associated with an improvement in mortality was identified. Further research is required to better understand the mechanism of this association.

Supplement.

eAppendix. Supplementary appendix

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The Atlas of Shared Learning

Sepsis pathway improvements across lancashire care homes, leading change.

The Community Infection Prevention Nurse (IPN) & Sepsis Lead at Lancashire County Council (LCC) led on a programme of work to implement a local community sepsis strategy and a sepsis training and development delivery programme. This has improved service provision for care homes across Lancashire.

Where to look

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection ( Singer et al., 2016 ). When people suffer from sepsis, the body’s immune system overcompensates causing widespread inflammation, swelling and blood clotting. These reactions can cause a significant reduction in blood pressure, which can decrease the blood supply to vital organs and starve them of oxygen. If not treated quickly, sepsis may lead to multiple organ failure and death. Whilst anyone is at risk of sepsis, older people are at greater risk of sepsis ( NHS England, 2015 ), as they are often immune compromised, living with comorbidities and prone to infections.

Across Lancashire there are over 400 residential and nursing care homes. Care home staff routinely report on numbers and types of infections experienced by care home residents. However, no baseline data exists on the numbers of suspected sepsis cases. Local data indicated that urinary tract and respiratory tract infections are two of the most common types of infections experienced by care home residents. These infections are often associated as a risk factor for sepsis and hospitalisation.

With this evidence base, as well as drawing from post infection reviews for MRSA and C. difficile infections and discussions with district nursing teams, the Infection Prevention Nurse & Sepsis Lead identified opportunities to improve the early identification and timely referral to treatment for care home residents with suspected sepsis. The opportunities for improvement included:

• Unwarranted variation in consistent, best practice and evidence based approaches to screening care home residents for suspected sepsis;
• Unwarranted variation in the use of language and clinical evidence to communicate to GPs and the local ambulance service that sepsis was suspected;
• Unwarranted variation in the timely escalation for appropriate healthcare.

These variations in practice were deemed to be contributing to poor experiences for care home residents.

What to change

The Infection Prevention and Control Team (IPCT) provide advice, support, training and education, and quality improvement to health and social care providers, as well as advice, support and assurance to local commissioners. Prior to 2017, across Lancashire care homes, there was not standardised provision of:

• A local sepsis strategy,
• A sepsis training and development delivery programme; or,
• Specialist advice, support and resources on sepsis.

The IPN & Sepsis Lead saw an opportunity to address this unwarranted variation to improve experiences and outcomes, as well as the use of resources across the area.

How to change

Following engagement with key stakeholders the IPN & Sepsis Lead initially:

• Carried out a sepsis training needs analysis for care homes and primary care with local CCGs to identify variation and gaps;
• Developed a Sepsis Strategy for Lancashire Care Homes 2017-2020 in consultation with 6 local CCGs, local care homes, North West Ambulance Service (NWAS), Advancing Quality Alliance (AQuA), NHS England National Sepsis Lead and a sepsis survivor, UK Sepsis Trust. The strategy was launched in July 2017;
• Developed evidence based sepsis training and development sessions for care homes;
• Promoted awareness of sepsis amongst key health and social care providers in the community.

Face to face training was rolled out with the support from a local critical care/sepsis team. Key objectives of the training for care staff were to:

• Understand the importance of infection prevention;
• Have increased knowledge of sepsis;
• Be knowledgeable, confident and skilled to detect, manage and escalate residents for time critical healthcare;
• Implement infection and risk principles with the support of tools such as NEWS2 and associated escalation protocols and;
• Have improved awareness of the care needs of residents with post-sepsis syndrome.

The use of consistent methods to detect, track and trigger suspected sepsis and/or cases of deterioration helps care home staff to manage residents effectively and improve outcomes.

Adding value

Better outcomes – Between September 2017 and January 2019, over 200 care staff from residential and nursing care homes have attended the sepsis training and development sessions. Care home staff across Lancashire are now implementing the approaches from the training in their care homes to improve experiences and outcomes for residents. It has been noted that the number of ambulance call outs to the home(s) and hospital admissions have reduced, with infections being treated earlier within the care homes. Suspected sepsis cases are being identified earlier and escalated appropriately for time critical healthcare. Communication and support for care home residents to return home after treatment in hospital for sepsis has also improved.

Better experience – Care home staff have welcomed the training and new approaches within their homes as they help with care being provided “in the right place, at “the right time”. Feedback from care home staff includes:

‘This course is excellent and should be rolled out to all care homes’

‘I would recommend this training to all people involved in care’

‘Improved my knowledge and understanding of sepsis greatly’

‘I am looking forward to applying the methods from this course in my care home’

Residents and families have also responded positively, anecdotally reporting that they appreciate prompt assessment and awareness of deterioration.

Better use of resources – Care home staff are now able to communicate NEWS2 scores to GPs and ambulance services together with a detailed account of the resident’s signs and symptoms of deterioration. This helps with communication and management across the pathway and appropriate decisions about where the residents should best be cared for can be made. Consistency in using the NEWS2 tool across primary care, community services and care homes is making communication far more effective and reducing duplication.

Challenges and lessons learnt for implementation

There has been high demand and enthusiasm amongst care home staff (both residential and nursing) to attend sepsis training in order to better identify and manage deterioration and suspected sepsis for care home residents.

The presentation of sepsis can be variable and difficult to detect and diagnose. Building a sepsis aware community across patient pathways is essential to reduce unavoidable morbidity and mortality from sepsis.

Incorporating single systems, such as NEWS2, to manage deterioration and sepsis consistently across pathways is essential for improving patient outcomes.

It can sometimes be challenging to take all observations for NEWS2 for residents who have certain conditions i.e. Dementia and Learning Disabilities. Using soft signs of deterioration, signs of infection and clinical judgement can help with identification and appropriate escalation.

Multi-media approaches are helpful when trying to reach lots of people across lots of organisations. Consider how your offer is supported digitally as well.

During 2019-2020, the sepsis training and development sessions will be rolled-out to include Learning Disability providers.

For more information contact

Jane Mastin Community Infection Prevention Nurse & Sepsis Lead Lancashire County Council [email protected]

• Care home (residential care/day care/supported living/home care)
• Community (including district nursing)
• Diagnostic or screening

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The public health agenda is embedded in pharmacy, yet topics such as emergency contraception or stop smoking support are as prevalent as ever. As well as our public health workshops, use this section to access a wide range of resources to assure and maintain your competence, all underpinned by the Declaration of Competence system.

If you are looking for the Quality payments page on Children's oral health please visit this link https://www.cppe.ac.uk/services/quality-payments

Introduction

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Introduction to Sepsis

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Sepsis (2024)

This e-assessment is linked with the six CPPE Sepsis case studies which can be found on the CPPE Sepsis gateway page. You will need to complete all six sepsis case studies before completing this assessment.

Why should I do this assessment?

Core and foundation learning

Early recognition of sepsis - community setting.

This short e-learning programme will help you to apply your knowledge on sepsis and determine how you can identify and manage sepsis safely using the National Early Warning Score (NEWS2). It is set in the community but contains learning relevant to all areas of practice.

This case study forms part of the Sepsis learning gateway . On this learning gateway page, you will find a range of learning resources which aim to increase your knowledge, skills, and confidence in relation to sepsis.

1h:00m (for events this includes pre and post event learning)

Early recognition of sepsis - hospital setting

This short e-learning programme will help you to apply your knowledge on sepsis, including the risk factors, signs and symptoms of sepsis, and determine how you can identify and manage sepsis safely. It is set in a hospital but contains learning relevant to all areas of practice.

Early recognition of sepsis - general practice setting

This short e-learning programme will help you to apply your knowledge on sepsis and understand the importance of clinical judgement when determining how to identify and manage sepsis safely. It is set in a general practice but contains learning relevant to all areas of practice.

Early recognition of sepsis - children

This short e-learning programme will help you to apply your knowledge on sepsis and determine how you can identify and manage sepsis safely. This case relates to a child but contains learning relevant to patients in all areas of practice.

Early recognition of sepsis - pregnancy

This short e-learning programme will help you to apply your knowledge on sepsis and determine how you can identify and manage sepsis safely. This case relates to a person who is pregnant but contains learning relevant to patients in all areas of practice.

Early recognition of sepsis - care home setting

This short e-learning programme will help you to apply your knowledge on sepsis and determine how you can identify and manage sepsis safely using the National Early Warning Score (NEWS2). It is set in a care home but contains learning relevant to all areas of practice.

National Confidential Enquiry into Patient Outcome and Death - Just say sepsis!

This National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report highlights the process of care for patients aged 16 years or older with sepsis. It contains nine case studies that cover pre-hospital care through to the initial management of sepsis.

Royal College of Physicians - National Early Warning Score (NEWS) 2

The NEWS aims to improve the detection of and response to clinical deterioration in patients with acute illness. The Royal College of Physicians page contains a link to the NEWS2 final report and NEWS scoring system, thresholds and triggers and observation charts.

Advanced learning

News2 - national early warning score online training resource.

This website offers free registration with an NHS email address. When registered, you will have an opportunity to learn about the implementation and use of the National Early Warning Score system, which has been introduced across the NHS.

Knowlex presentation - An Hour on Sepsis by Dr. Matt Inada-Kim

This presentation, hosted on YouTube, is delivered by Matt Inada-Kim, a Consultant Acute Physician. More about Matt and his work can be found on the NHS England website.

Think Sepsis - identifying and managing sepsis

“THINK SEPSIS” is a Health Education England programme aimed at improving the diagnosis and management of those with sepsis.

Further reading

The surviving sepsis campaign bundle, the surviving sepsis campaign:international guidelines for management of sepsis and septic shock, the uk sepsis trust - clinical resources, nhs england - cross-system sepsis action plan, world sepsis day website, nhs england - improving outcomes for patients with sepsis, nice - sepsis: recognition, diagnosis and early management, nice - fever in under 5s: assessment and initial management.

This guideline covers the assessment and early management of fever with no obvious cause in children aged under five.

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• GP Training

Sepsis case study

By Dr Sean Brink on the 27 July 2016

A case of a 39-year-old man who presented with swelling and pain in his scrotum and penis highlights the importance of remaining vigilant to the risk of sepsis, red flags for sepsis in adults and the Sepsis Six care bundle.

Sepsis causes 37,000 deaths annually in the UK, a five-fold higher mortality than STEMI or  stroke . 1  Sepsis is a medical emergency, for every hour antibiotic administration is delayed there is an 8% increase in mortality. 2   NICE has published new guidance on recognition, diagnosis and management of severe sepsis . 3

A 39-year-old man felt unwell overnight with swelling and pain in his scrotum and penis. In the morning he felt breathless and had blood-stained fluid oozing from his penis. He called 999 and the ambulance crew took him to accident and emergency. The patient admitted that he had not attended earlier because he was frightened and because he was sole guardian of his teenage son, who had to come with him.

The patient was cared for in a cubicle in A&E. As a general practice trainee my first contact with him was when a concerned nursing assistant showed me his ECG, which revealed a sinus tachycardia with a rate of 140bpm.

The patient had no significant medical or sexual history, regular medications or allergies, and his last sexual contact was over two years ago.

Initial investigations

Observations showed a respiratory rate of 39 per minute with BP 120/75, oxygen saturations of 97% in air and tympanic temperature of 37.9C. Capillary blood glucose was 13.4mmol/l with no history of diabetes.

The patient’s arterial blood gas showed a marked compensated alkalosis with a lactate 3.9mmol/l. Venous blood results showed a CRP of 535 mg/l, urea of 11 mmol/l and creatinine 200 µmol/l.

The patient had Fournier’s gangrene. Treatment followed the Sepsis Six care bundle — an initial resuscitation bundle designed for secondary care to offer basic intervention within the first hour of identification (box 2). 1

Oxygen therapy, IV fluid resuscitation with crystalloid fluid through large bore cannulae, and analgesia were given. Blood cultures were taken. After 95 minutes in A&E the patient was taken to theatre for penile shaft and scrotal skin debridement. After 24 hours he had lower abdominal and thigh incisions. He spent nine days in the high dependency unit.

Guidelines for the management of patients in primary care are shown in box 3.

Outcome and follow up

Beta-haemolytic group A streptococcus was identified from the patient’s blood cultures. Antibiotic therapy was guided by the sensitivities.

The patient was followed up in the local plastic surgery department six weeks after leaving hospital for consideration of split skin grafting of unhealed areas.

Learning points

Healthcare professionals must remain vigilant to the risk of sepsis. It can occur in patients who are expected to be least at risk. In this case, sepsis was only identified when an ECG showed a marked tachycardia in an unassuming young patient.

It is important to triage effectively and review channels of communication so that patients feel able to contact us.  The UK Sepsis Trust  have produced a useful symptom checker card for patients, which can be downloaded from:  sepsistrust.org/uk .

Important:  NICE recommends asking 'Could this be sepsis?’ if patients present with signs or symptoms that indicate infection, even if they do not have a high temperature. See NICE algorithm for assessing adults

In Fournier’s gangrene, the infection spreads along well-described fascial planes of the perineum, scrotum and penis, often with involvement of the thighs and lower abdomen.

Fournier’s gangrene fulfils the criteria for necrotising fasciitis; a bacterial infection rapidly spreading through cutaneous tissue planes. Necrotising fasciitis is uncommon, with only 24 patients diagnosed in six years in one tertiary centre (group A streptococcus was the principal organism in a third of these cases). 4  

The hospital where this patient presented had 17 cases in nine years, of which eight cases related to the pelvic region and thighs.

Since 2001 the  Surviving Sepsis Campaign  aimed to improve survival.  National guidance for hospitals was published in 2005 . 5  

In 2013, the UK Parliamentary and Health Service Ombudsman  highlighted shortcomings  in initial assessment of patients with sepsis and delay in emergency treatment, which led to missed opportunities to save lives. 6  

Improvements have been made since then. For example, IT desktop toolkits for GPs are being created by the  UK Sepsis Trust . 1  NHS England, the Academy of Royal Medical Colleges and the Department of Health are working to reduce avoidable mortality. 7

Take a test on this article and claim your certificate on MIMS Learning

• Dr Sean Brink, GP in East Sussex, United Kingdom
• The UK Sepsis Trust. Toolkit:  General Practice management of sepsis . Available from: sepsistrust.org/wp-content/uploads/2015/08/1409322498GPtoolkit2014.pdf
• Kumar A, Roberts D, Wood KE et al.  Crit Care Med 2006; 34:1589–96 .
• NICE.  Sepsis: recognition, diagnosis and early management . NG51. NICE, London, 2016.
• Glass G, Sheil F, Ruston JC, et al.  Ann R Coll Surg Engl 2015; 97: 46-51 .
• Dellinger RP, Carlet JM, Masur H, et al.  Crit Care Med 2004; 32(3):858–73 .
• Parliamentary and Health Service Ombudsman.  Time to act. Severe sepsis: rapid diagnosis and treatment saves lives . 2013.
• NHS England.  Cross-system sepsis programme board . 19 March 2015.

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Open Access

Peer-reviewed

Research Article

Severe Maternal Sepsis in the UK, 2011–2012: A National Case-Control Study

Affiliation National Perinatal Epidemiology Unit, University of Oxford, Oxford, United Kingdom

Affiliation Department of Anaesthesia, Northwick Park Hospital, Harrow, United Kingdom

Affiliation Bradford Royal Infirmary, Bradford Hospitals NHS Trust, Bradford, United Kingdom

Affiliation St. Michael's Hospital, University Hospitals Bristol NHS Trust, Bristol, United Kingdom

* E-mail: [email protected]

• on behalf of the United Kingdom Obstetric Surveillance System
• Colleen D. Acosta, 
• Jennifer J. Kurinczuk, 
• D. Nuala Lucas, 
• Derek J. Tuffnell, 
• Susan Sellers, 
• Marian Knight, 

• Published: July 8, 2014
• https://doi.org/10.1371/journal.pmed.1001672
• Reader Comments

In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK.

Methods and Findings

A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2–5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR = 1.82; 95% CI 1.82–2.51), were primiparous (aOR = 1.60; 95% CI 1.17–2.20), had a pre-existing medical problem (aOR = 1.40; 95% CI 1.01–1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR = 12.07; 95% CI 8.11–17.97), or had an operative vaginal delivery (aOR = 2.49; 95% CI 1.32–4.70), pre-labour cesarean (aOR = 3.83; 95% CI 2.24–6.56), or cesarean after labour onset (aOR = 8.06; 95% CI 4.65–13.97). Median time between delivery and sepsis was 3 d (interquartile range = 1–7 d). Multiple pregnancy (aOR = 5.75; 95% CI 1.54–21.45) and infection with group A streptococcus (aOR = 4.84; 2.17–10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women, <9 h—between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%).

Conclusions

For each maternal sepsis death, approximately 50 women have life-threatening morbidity from sepsis. Follow-up to ensure infection is eradicated is important. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of early administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis in peripartum women, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency.

Please see later in the article for the Editors' Summary

Editors' Summary

Every year, nearly 300,000 women worldwide die during pregnancy or labour, or shortly after. According to a recent World Health Organization estimate, sepsis (blood poisoning) is responsible for 10.7% of these maternal deaths. Sepsis is caused by an inappropriate immune response to an infection. Normally, when bacteria or other microbes enter the human body, the immune system efficiently destroys the invaders. In sepsis, the immune system goes into overdrive, and the chemicals it releases into the blood to combat infection trigger widespread inflammation. This inflammation leads to the formation of small blood clots and leaky blood vessels that block the flow of blood to the vital organs. In the most severe cases (septic shock), blood pressure falls to dangerously low levels, multiple organs fail, and the patient can die. Symptoms of sepsis include fever, rapid breathing, and a fast heart rate. Sepsis, which often progresses rapidly, can be treated in its early stages with antibiotics alone. People with severe sepsis need to be admitted to an intensive care unit, where their vital organs can be supported while the infection is treated.

Why Was This Study Done?

Deaths from maternal sepsis mainly occur in low- and middle-income countries, but the rate of such deaths is increasing in countries with advanced healthcare systems. In the UK, for example, the incidence (the number of cases) of fatal maternal sepsis has increased markedly over the past two decades, and although the absolute risk of maternal death from sepsis is low, increasing numbers of women are experiencing severe maternal sepsis. To avoid preventable maternal illness and death in the UK, it is essential that clinical management and infection control strategies for maternal sepsis are improved. Here, to learn more about the incidence of maternal sepsis, the causative organisms and sources of infection, and the risk factors for maternal sepsis in the UK, the researchers undertake a national case-control study of severe maternal sepsis. A case-control study compares the characteristics of individuals with and without a given disease.

What Did the Researchers Do and Find?

For this study, clinicians in all the UK obstetrician-led maternity units (obstetricians care for women throughout pregnancy, labour, and the post-labour period) sent information about every woman who developed severe sepsis between June 2011 and May 2012 (365 cases) and about two unaffected (control) women per case to the United Kingdom Obstetric Surveillance System (UKOSS). Using this information and data on the number of maternities in the UK during this 12-month period, the researchers calculated that the incidence of severe sepsis was 4.7 per 10,000 maternities. Seventy-one women with severe sepsis (19.5% of cases) developed septic shock, and five women (1.4% of cases) died. The most common source of sepsis (implicated in about a third of cases) was a genital tract infection. Statistical analyses identified several risk factors for severe maternal sepsis, including having a fever or taking antibiotics in the two weeks preceding sepsis and all types of operative delivery (including cesarean delivery). Importantly, although Escherichia coli was the most common causative organism in severe maternal sepsis (present in a fifth of cases), infection with group A streptococcus was strongly associated with progression to septic shock. Moreover, in half the women with a group A streptococcal infection, severe sepsis was diagnosed within two hours of the first signs of a systemic inflammatory response.

What Do These Findings Mean?

These findings show that for every death from maternal sepsis in the UK, about 50 women develop life-threatening severe sepsis, that the onset of severe sepsis is very rapid, and that women who have recently had an infection are at particularly high risk of developing maternal sepsis. Although some pregnant women who developed severe sepsis during the study period may not have been included in the study, these findings have important clinical implications for the management of maternal sepsis in the UK and elsewhere. The findings suggest that pregnant or recently pregnant women with an infection need closer attention than women who are not pregnant, and adequate follow-up to ensure eradication of the infection. The findings also highlight the importance of giving high-dose intravenous antibiotics to anyone with suspected sepsis within an hour of admission to hospital as recommended by the international Surviving Sepsis Campaign, an initiative that was developed to improve the management, diagnosis, and treatment of sepsis. Finally, these findings suggest that signs of severe sepsis, particularly in women with a confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001672 .

• The UK National Health Service Choices website has information about sepsis
• The international Surviving Sepsis Campaign guidelines for the treatment of sepsis are available through the campaign's website
• The Sepsis Alliance , a US not-for-profit organization, also provides information about sepsis for patients and their families (in English and Spanish), including information about maternal sepsis and several personal stories about maternal sepsis (see the stories of Alanna Basinger, Alisa Proctor, Sandy C, and Natalie Banathy)
• The not-for profit UK Sepsis Trust is another useful source of information about sepsis that includes patient stories
• MedlinePlus provides links to additional resources about sepsis (in English and Spanish)
• UKOSS provides more information about its national case-control study on severe maternal sepsis in the UK

Citation: Acosta CD, Kurinczuk JJ, Lucas DN, Tuffnell DJ, Sellers S, Knight M, et al. (2014) Severe Maternal Sepsis in the UK, 2011–2012: A National Case-Control Study. PLoS Med 11(7): e1001672. https://doi.org/10.1371/journal.pmed.1001672

Academic Editor: Nicholas M. Fisk, University of Queensland, Australia

Received: February 21, 2014; Accepted: May 28, 2014; Published: July 8, 2014

Copyright: © 2014 Acosta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All data underlying the findings are available by request to the National Perinatal Epidemiology Unit Data Sharing Committee.

Funding: This article presents independent research funded by the National Institute for Health Research (NIHR) under the “Beyond maternal death: Improving the quality of maternity care through national studies of ‘near-miss’ maternal morbidity” program (Programme Grant RP-PG-0608-10038). Marian Knight is funded by a National Institute for Health Research (NIHR) Professorship. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: SS is Chair of the Claims Advisory Committee at the Medical Protection Society for which she receives an honorarium. All other authors have declared that no competing interests exist.

Abbreviations: aOR, adjusted odds ratio; IQR, interquartile range; OR, odds ratio; SIRS, systemic inflammatory response syndrome; UKOSS, United Kingdom Obstetric Surveillance System; uOR, unadjusted odds ratio

Introduction

Maternal death from sepsis is increasing in countries with advanced healthcare systems [1] – [4] , and sepsis is estimated to cause 9.7%, 11.6%, and 7.7% of maternal deaths in Africa, Asia, and Latin America and the Caribbean, respectively [5] . Sepsis is now the leading cause of direct maternal death in the United Kingdom [2] . In 2006–2008, the UK maternal mortality rate from sepsis was 1.13/100,000 maternities, a rate not seen since the early 1970s [2] , [6] . Underlying this trend is an increasing number of maternal deaths from group A streptococcal infection, most recently accounting for 50% of direct maternal sepsis deaths. This trend has also been observed in the Netherlands [7] . Although the absolute risk of maternal death from sepsis is low, an increase in maternal mortality implies a greater number of women with severe, life-threatening illness. Recent work has suggested an approximate doubling of the incidence of maternal sepsis in the US since 2003 [4] .

Key information gaps in the understanding of this pressing problem are the number of women affected, causative organisms, sources of infection, and risk factors for severe sepsis and poor outcomes such as septic shock. Sepsis progresses along a spectrum of severity, so clarity about these factors has urgent implications for clinical management and infection control strategies to avoid preventable maternal deaths.

The objectives of this national prospective case-control study were to estimate the incidence, describe the causative organisms and sources of infection, and identify the risk factors for severe maternal sepsis in the UK. This information will inform strategies to improve outcomes for mothers and their babies through further development of guidelines for prevention and management of sepsis in pregnancy in the UK.

Research Ethics Committee Approval

This study was approved by the London Research Ethics Committee (ref 10/H0717/20).

Study Design

We undertook a national prospective case-control study of all peripartum women diagnosed with severe sepsis (including septic shock), irrespective of the source of infection, together with control women, in all obstetrician-led maternity units in the UK from June 1, 2011, to May 31, 2012. All UK hospitals with obstetrician-led maternity units participated in the study (168 in England, nine in Northern Ireland, 16 in Scotland, 14 in Wales, three in the Crown Dependencies). The study included a descriptive analysis of the incidence, causative organisms, sources of infection, and outcomes of severe sepsis, and a case-control analysis of factors associated with severe sepsis and septic shock. In order to assess risk factors for developing severe sepsis, all cases were compared with non-septic controls. To assess the risk of progression to septic shock, cases with a diagnosis of septic shock were compared to all other cases with severe sepsis that did not develop into septic shock.

Data Source and Definitions

This study was conducted using the United Kingdom Obstetric Surveillance System (UKOSS). The UKOSS methods have been described elsewhere [8] . In brief, the UKOSS network of collaborating clinicians includes up to four nominated reporting clinicians (obstetricians, midwives, anaesthetists, and risk managers) in each obstetrician-led maternity unit in the UK. Nominated clinicians coordinate case reports from all clinicians in their units, and for this study were asked to report, via a monthly report card, how many women met the case definition for severe sepsis. Clinicians were asked to return all cards, including those with no cases to report, in order for participation to be monitored. Clinicians who reported a case were then sent a data collection form with a unique UKOSS identification number, requesting further detailed information on obstetric and medical history, diagnosis, management, and outcomes. Reporting clinicians were also asked to complete a data collection form for two women meeting the control definition. All data collected were new, and not based on routinely collected hospital admissions data. If completed data collection forms were not returned, up to four further reminders were given (after 6 wk, a second form was sent out, and a third form 4 wk thereafter; if there was still no response after a further 4 wk, the clinician was contacted by telephone). Overall, UKOSS has a 93% card return rate [8] . Where data were missing or invalid, clinicians were contacted for the correct information. All data were double entered into a customised database, and cases were verified to ensure that they met the case definition and to exclude duplicate reports.

Since there is currently no standardised definition for severe sepsis in pregnant and peripartum women, the study definition was developed based on previous literature and by consensus of the UKOSS steering committee [8] . In the non-obstetric population, consensus definitions of sepsis severity (systemic inflammatory response syndrome [SIRS], sepsis, severe sepsis, and septic shock) were developed in 1992 ( Box 1 ) [9] . These definitions and subsequent improvements, however, are often not applicable to pregnant and peripartum women since clinical signs and symptoms of severe infection differ in this population. Specifically, SIRS can be a sign of ruptured membranes and changing biochemistry associated with labour and delivery, as well as a clinical marker of severe infection. Therefore, the clinical parameters of SIRS in the presence of an infection are often altered in the obstetric population. We adopted the “obstetric SIRS” criteria from a 2001 study of severe obstetric morbidity [1] and took into account clinical management (level 2 or level 3 critical care [10] ) and whether the woman died. The full case definition for this study is listed in Box 1 . Controls were women who did not have severe sepsis and delivered immediately before each case in the same hospital. For women transferred to higher-level hospitals, controls were drawn from the delivery hospital. The source population was thus all women giving birth in the UK.

Box 1. General Sepsis Definitions and Study Definition of Severe Sepsis

General sepsis definitions*.

SIRS —Two of the following: temperature >38°C or <36°C, heart rate >90 beats/min, respiratory rate >20 breaths/min, or PaCO 2 <32 mmHg (4.3 kPa), white cell count >12,000 cells/µl or <4,000 cells/µl, or 10% immature/band forms.

Sepsis— SIRS with infection.

Severe sepsis— Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

Septic shock— Sepsis associated with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities as listed for severe sepsis. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.

Study Definition of Severe Sepsis

Applied to women at any point in pregnancy and up to 6 wk postpartum:

• Death related to infection or suspected infection
• Any woman requiring level 2 or level 3 critical care (or obstetric high-dependency unit–type care) with severe sepsis or suspected severe sepsis
• Temperature >38°C or <36°C, measured on two occasions at least 4 h apart
• Heart rate >100 beats/min, measured on two occasions at least 4 h apart
• Respiratory rate >20/min, measured on two occasions at least 4 h apart
• White cell count >17×10 9 /l or <4×10 9 /l or with >10% immature band forms, measured on two occasions

*Source: 1992 American College of Chest Physicians/Society of Critical Care Medicine definitions [9] .

Level 2 care is defined as patients requiring more detailed observation or intervention, single failing organ system, or postoperative care, and higher levels of care. Level 3 care is defined a patients requiring advanced respiratory support alone or basic respiratory support together with support of at least two organ systems. This level includes all complex patients requiring support for multi-organ failure. [10]

Statistical Analyses

Stata statistical software 11 (StataCorp) was used for all analyses. The incidences of severe maternal sepsis and septic shock with 95% confidence intervals were calculated using the number of maternities reported in the most recent national birth data (2011) [11] – [13] as the denominator, since data are not available on the actual population at risk (number of women who have had a pregnancy, including women who have had miscarriages or pregnancy terminations). In these data, a maternity is defined as any woman giving birth to a live or stillborn infant of greater than 24 completed weeks of gestation. Women with signs and symptoms of sepsis prior to delivery were classified as an antepartum cases. Sources of infection, causative organisms, and sepsis severity characteristics were tabulated for all cases, and stratified according to partum status, as pathogenesis is known to differ between pregnant and postpartum women [14] . Groups were compared using a chi-square test for categorical variables; corresponding p -values are reported in the text.

For risk factor analyses, sociodemographic, medical history, and delivery characteristics with a priori evidence of an association with sepsis were compared between cases and controls, and between cases with and without septic shock. Sources of infection and causative organisms were also assessed as risk factors in the latter comparison. Comparisons were made using Pearson's chi-square and Fisher's exact tests where appropriate. All p -values were two-sided, and a p -value of <0.05 was considered statistically significant. The proportion of missing data in this study was very low; the only variables with substantial missing data (>1%) were source and organism of infection, and socio-economic group. It is common to have sepsis patients without a clear source of infection and/or cultures that are negative [15] , and a previous UKOSS study found that women with unknown socio-economic information had significantly higher odds of severe maternal morbidity [16] . It is not likely therefore that missing data for these variables were missing at random, and thus a missing data technique such as multiple imputation would not have been appropriate. In order to account for the missing data for sources of infection, causative organisms, and socio-economic group, the subcategories of “unknown” and “no laboratory-confirmed infection” were included for these variables in all analyses.

The odds of severe sepsis and septic shock associated with each risk factor were estimated using univariable unconditional logistic regression and were then adjusted using multivariable unconditional logistic regression. (Since convenience matching was used, and thus the cases and controls were not matched according to criteria relevant to the analysis, conditional logistic regression was not needed [17] .) For both the severe sepsis and septic shock outcome groups, factors were adjusted in two stages. First, all a priori sociodemographic and medical history factors, with the exception of previous cesarean delivery and previous pregnancy problem (as these were dependent on parity) and partum status (since the control population was only women who had delivered), were included in a primary model. Second, delivery factors were then adjusted for a priori risk factors using a more parsimonious approach in order to avoid overadjustment or substantial colinearity given the large number of variables; results were adjusted only for a priori factors from the primary model that were known risk factors, were significant in the primary model at p <0.05, or were plausible confounders as identified in previous literature. Delivery characteristics were evaluated for postpartum cases only, as this set of risk factors pertained specifically to delivery.

In the multivariable models, major pre-existing medical problems and complications of delivery were first included into the models as separate categories in order to check the significance of any conditions expected to have an association with severe sepsis. No significant differences in individual conditions between cases and controls were identified. As the numbers of individual pre-existing medical problems and complications of delivery were very small—with subsequent insufficient power to confidently detect statistical differences between cases and controls for these small groups—individual conditions were combined into aggregate variables. Diabetes, history of pyelonephritis/urinary tract infection, and history of sexually transmitted infection were retained as separate categories because these factors have been cited as independent risk factors for sepsis [4] , [18] .

Results of both stages of adjustment are reported as unadjusted odds ratios (uORs) and adjusted odds ratios (aORs) and their 95% CIs for severe sepsis. For ease of presentation of risk factors for progression to septic shock, results are reported only for factors included in the final adjusted models. Likelihood ratio tests with a significance level of p <0.01 were used to check for interactions between variables; no significant interactions were identified in the final adjusted models.

Sample Size and Power

Within a 1-y study period, we anticipated approximately 316 cases of severe sepsis based on an estimated incidence of four per 10,000 maternities [1] . For the severe sepsis risk factor analysis, with two controls per case, and for a risk factor prevalence of at least 5% in control women, the study was estimated to have had 80% power at p <0.05 (two-sided) to detect a statistically significant odds ratio (OR) of 2.3 or greater. The actual number of cases and controls identified during the study period of 12 mo generated an estimated power of 80% at the 5% level of significance to detect an OR of 2.1 or greater, for the same risk factor prevalence level. For the septic shock risk factor analysis, for a risk factor prevalence of at least 15% in women without septic shock, the analysis had 80% power at the 5% level of significance to detect an OR of 2.6 or greater.

During the study period, all 214 UK hospitals with obstetrician-led maternity units participated in UKOSS, representing 100% participation. There were a total of 486 cases of severe sepsis reported, of which data collection was complete for 90% ( Figure 1 ), and data were obtained for 757 controls. Of the reported cases, 29 did not meet the case definition and were excluded from the study; of these 29 cases, 11 had only one control form returned, and 20 control forms had incomplete data and were thus excluded, leaving 27 additional controls that were included in the study. There was a total of 365 confirmed cases of severe sepsis out of 780,537 maternities in the UK [11] – [13] , representing an incidence of 4.7 per 10,000 maternities (95% CI 4.2–5.2). Seventy-one women (20%) developed septic shock, which represents an incidence of 0.91 per 10,000 maternities (95% CI 0.71–1.15).

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https://doi.org/10.1371/journal.pmed.1001672.g001

Sources, Causative Organisms, and Severity

Laboratory-confirmed infection was reported for 233 (63.8%) severe sepsis cases, and a source of infection was identified for 270 cases (74.0%); 60 cases (16.4%) had neither a source of infection or causative organism identified. The distribution of sources of infection, causative organisms, and severity characteristics are shown in Table 1 and Figures 1 and 2 . Overall, the largest proportion of cases was due to genital tract infection (31.0%), and the most common organism causing infection was Escherichia coli (21.1%). However, the distributions of both the infection source and the causative organism differed significantly between women with antepartum versus postpartum sepsis ( p <0.0001 for both), as did the risk of septic shock. Readmission (for reasons other than delivery) also differed significantly between the two groups; 108 (48%) women with postpartum sepsis were readmitted, compared to six (5%) women with antepartum sepsis ( p <0.0001). Of all cases, 286 (78%) received level 2 or intensive care, and five women died ( Table 1 ). Of the women who died, two had infection with E. coli , and three women had an unknown causative organism. Twenty-nine (8%) women with severe sepsis had either a miscarriage or a termination of pregnancy. For women diagnosed with severe sepsis antenatally, five of 137 infants were stillborn (3.6%), and seven died in the neonatal period (5.1%). Fifty-eight infants (42.3%) were admitted to neonatal intensive care.

Stacked bars represent the number of cases with specific causative organisms according to infection source and mode of delivery categories. Data are mutually exclusive.

https://doi.org/10.1371/journal.pmed.1001672.g002

https://doi.org/10.1371/journal.pmed.1001672.t001

Time Course

The median gestational age at antenatal sepsis diagnosis was 35 wk (interquartile range [IQR] 27–40 wk). The median diagnosis-to-delivery interval for women with antenatal sepsis was 0 d (IQR 0–36 d). The median time between delivery and sepsis for postpartum cases was 3 d (IQR 1–7 d). There were 296 cases with recorded dates and times for the first sign of SIRS and the severe sepsis diagnosis; for 245 (83%) severe sepsis cases and for 49 (85%) septic shock cases, there was <24 h between the first sign of SIRS and the diagnosis of severe sepsis; and for 264 (89%) severe sepsis cases and for 55 (95%) septic shock cases there was <48 h between the first sign of SIRS and the diagnosis of severe sepsis. For 95 (86%) women who were readmitted there was <24 h between the first sign of SIRS and diagnosis of severe sepsis. Additionally, for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women <9 h—between the first sign of SIRS and the diagnosis of severe sepsis.

Risk Factors for Severe Sepsis

A priori sociodemographic and medical history characteristics of women with severe sepsis compared to control women are listed in Table 2 . After adjustment and compared to controls, women who were of black or other minority ethnic origin, were primiparous, had a pre-existing medical problem, or had a febrile illness or were taking antibiotics in the 2 wk prior to presentation were at significantly increased odds of severe sepsis. There was no statistically significant association between premature rupture of membranes and severe sepsis in either antenatal cases ( n  = 20; aOR = 1.72; 95% CI 0.98–3.02) or postnatal cases ( Table 3 ). In addition to significant a priori factors, the following factors significantly increased the odds of severe sepsis in women with postpartum sepsis: having an operative vaginal delivery (aOR = 2.49; 95% CI 1.32–4.70), having a pre-labour cesarean section (aOR = 3.83; 95% CI 2.24–6.56) or a cesarean section after the onset of labour (aOR = 8.06; 95% CI 4.65–13.97), or having a complication of delivery (aOR = 1.69; 95% CI 1.09–2.63) ( Table 3 ). Of note, of all women who had a cesarean section, 96.6% of cases and 94.8% of controls received prophylactic antibiotics at delivery.

https://doi.org/10.1371/journal.pmed.1001672.t002

https://doi.org/10.1371/journal.pmed.1001672.t003

Risk Factors for Septic Shock

A priori sociodemographic, infection, and delivery characteristics amongst woman who had septic shock, compared to women with severe sepsis but not septic shock, are described in Table 4 and Figure 3 . After adjustment for all a priori and infection factors in the model, multiple pregnancy and group A streptococcus as the causative organism were significantly associated with an increase in the odds of progression from severe sepsis to septic shock. Before adjustment for group A streptococcal infection, spontaneous vaginal delivery (aOR = 3.85; 95% CI 1.35–10.96) and operative vaginal delivery (aOR = 3.12; 95% CI 1.03–9.57) were significantly associated with an over 3-fold increase in the odds of progression to septic shock.

Bars represent the proportion, and whiskers the corresponding 95% CIs, of women with septic shock versus no shock, distributed according to causative organism.

https://doi.org/10.1371/journal.pmed.1001672.g003

https://doi.org/10.1371/journal.pmed.1001672.t004

Severe Genital Tract Sepsis

When the logistic models were re-run specifically including only cases with genital tract infection ( n  = 113) compared to controls, women who were black or from another minority ethnic group (aOR = 2.08; 95% CI 1.27–3.40), had a multiple pregnancy (aOR = 5.29; 95% CI 1.31–21.44), or had a febrile illness or were taking antibiotics in the 2 wk prior to delivery (aOR = 11.70; 95% CI 6.83–20.07) had significantly increased odds of severe sepsis. After adjusting for a priori factors, compared to women who had a spontaneous vaginal delivery, and controlling for illness prior to delivery, women who had a pre-labour cesarean section (aOR = 2.67; 95% CI 1.16–6.14), cesarean section after the onset of labour (aOR = 6.91; 95% CI 2.96–16.13), or a complication of delivery (aOR = 2.10; 95% CI 1.09–4.05) had significantly increased odds of severe sepsis. Of women with severe genital tract sepsis, 27 (23.9%) developed septic shock. Infection with group A streptococcus (aOR = 3.30; 95% CI 1.03–10.53) was the single factor associated with an increased odds of septic shock.

We found that for each maternal sepsis death in the UK, approximately 50 women have life-threatening morbidity from sepsis, and the onset of severe sepsis from SIRS occurs very rapidly. Genital tract and urinary tract infections are the predominant sources of infection; all modes of operative delivery carry significant risks for severe sepsis; and whilst the largest proportion of cases of severe sepsis is caused by E. coli , outcomes are significantly worse for women with group A streptococcal infection. Importantly, women who are treated with antibiotics in the perinatal period are at significant risk of severe sepsis, suggesting that a significant proportion of infections progress even following antibiotic treatment. These findings highlight a number of key messages for clinical practice in both primary and secondary care, with the high levels of life-threatening morbidity identified indicating that pregnant or recently pregnant women with suspected infection need closer attention than women who are not pregnant.

Strengths of this study include the robust design and participation of 100% of the maternity units in the UK, thus many limitations concerning regional differences, population size, and selection bias were minimised. It is possible that some women with severe sepsis in pregnancy were not admitted to maternity units, and thus not included in the study population. However, in the majority of cases, an obstetrician would be consulted about the care of such women, and these patients are thus likely to be brought to the attention of maternity services. In addition, while the distribution of antepartum sepsis cases is in keeping with the UK Confidential Enquiry into Maternal Deaths, with the majority of sepsis deaths occurring later in pregnancy [2] , since UKOSS data is collected from maternity units it may be that first trimester cases were under-captured; however, it was not possible to audit this. Lastly, results of the distribution of causative organisms were limited by the proportion of women with a clinical diagnosis of sepsis, but no identified organism. Failure to identify a causative organism in a proportion of cases is, however, to be expected [15] and therefore may not be regarded as a limitation, given that there is currently no other UK study that has elucidated the distribution of causative organisms for severe maternal sepsis.

The incidence rate and risk factors identified concur with previous studies of severe maternal sepsis [1] , [2] , [4] , [19] , [20] , and the results are likely to be generalisable to other high-resource settings such as the US and the Netherlands, which have experienced similar increases in severe maternal morbidity and mortality from sepsis [3] , [4] , [21] . A recent national study in the US found that maternal mortality from sepsis increased by 10% per year from 1998 to 2008 [21] , and another large population-based cohort study in the US found that the incidence of severe maternal sepsis in 2005–2007 was nearly double the 2003 estimate [4] . In addition, risk factors identified in our study, such as black or other minority ethnic group, primiparity, and multiple pregnancy, were also identified in the two US-based studies. These similarities suggest that our findings have generalisable implications for clinical practice, guideline development, and further study of causative organisms. Many clinical messages relate to basic care and can also be generalised to obstetric services in lower-resource countries. The limitations that apply to all case-control studies using multivariable analysis also apply to this study, and the level of evidence should be considered on this basis.

With further regards to incidence rates, Waterstone and colleagues, in the only other large population-based study of severe maternal sepsis in the UK, reported an incidence of 4.0 (95% CI 2.0–6.0) per 10,000 maternities in southwest England during the period from 1997 to 1998 [1] . The incidence of 4.7 per 10,000 maternities identified in the current study represents a 15% increase, which corresponds to the increase in maternal deaths from sepsis in the UK since this period (0.85 to 1.13 per 100,000 maternities [2] ). An incidence of 4.7 is also within the range of other population-based studies of severe maternal sepsis, most recently 2.1 per 10,000 in the Netherlands [20] , 2.1 per 10,000 in Scotland [19] , and 4.9 per 10,000 in the US [4] . It is interesting to note that incomplete information (and thus underreporting) was discussed as a limitation of the Dutch study [20] ; it is possible, therefore, that the rate in the Netherlands might be closer to that found in this study.

Severe sepsis in pregnancy presents in primary care, and the previously undescribed association between antibiotic prescription in the perinatal period and risk of severe sepsis suggests that primary care practitioners should have a low threshold for referral of women in pregnancy with signs of infection. Over 40% of women with severe sepsis had a febrile illness or were taking antibiotics prior to presentation, which suggests that at least a proportion were not adequately diagnosed, treated, or followed up. It cannot be assumed that antibiotics will prevent progression to severe sepsis, and safety net checks—for example, follow-up appointments or instructions to return if symptoms do not resolve—should therefore be in place to make sure a pregnant woman treated for infection has recovered. Simply prescribing antibiotics alone may not be appropriate. This message applies equally to secondary care; there is a need to ensure that follow-up happens to ensure that treatment is effective.

As sepsis progresses along a spectrum of severity, the occurrence of life-threatening sepsis represents the severest end short of a maternal death, and therefore only the “tip of the iceberg” of serious maternal morbidity. Failure to recognise the severity of an infection is a ubiquitous factor in the progression to severe sepsis [2] , [22] , [23] . Intensivists have the most training in sepsis management; however, initial presentation is often to general practitioners or to accident and emergency medical staff with less awareness of the signs and symptoms of sepsis, or of the rapidity with which it may progress to severe sepsis in the obstetric population [24] . In our study population, for most women with severe sepsis there was less than 24 h between the first sign of SIRS and the diagnosis of severe sepsis, and for most women with a group A streptococcal infection there was less than 9 h between the first sign of SIRS and severe sepsis, with half having less than 2 h between the first signs and diagnosis.

The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign's guidelines in pregnancy, and the recommendation for administration of high-dose intravenous antibiotics within 1 h of admission for anyone with suspected sepsis [25] .

A challenge in all previous studies of maternal sepsis has been to assess the temporality of mode of delivery in relation to infection and sepsis. Our study shows that after controlling for illness before delivery, as well as clinical risk factors such as premature rupture of membranes, all modes of operative delivery (operative vaginal, pre-labour cesarean, and cesarean after the onset of labour) were independent risk factors for severe sepsis. Even though antibiotic prophylaxis at cesarean section is routine practice in the UK, these results suggest that women are still at heightened risk of severe sepsis, despite the administration of antibiotics, and emphasise the importance of attention to prophylaxis particularly in emergency deliveries. The risk associated with operative vaginal delivery confirms findings from a previous study [19] , and suggests there is a need for further investigation of the role of prophylactic antibiotics as well as stringent attention to infection control measures for these deliveries.

The different patterns of infection we observed in antenatal and postnatal women suggest that overall greater consideration needs to be given to the source of infection, and therefore the most appropriate antibiotic to prescribe. This study highlights that urinary tract infection remains an important cause of severe sepsis, particularly antenatally, so prompt treatment and follow-up in primary care to ensure that the infection is eradicated is important. This finding was not identified in the most recent UK Confidential Enquiry into Maternal Deaths [2] , and provides further evidence of the importance of investigation of severe morbidity as well as mortality in high-resource settings to generate actions to prevent severe disease.

Our results indicate that although severe sepsis is more common following cesarean delivery, women delivering vaginally are at heightened risk of group A streptococcal infection, and those that are infected with group A streptococcus are at significantly increased risk of progression to septic shock compared with women infected with another organism. These results are consistent with the recent trend in maternal sepsis deaths in the UK; 50% of direct genital tract sepsis deaths in the most recent Confidential Enquiry into Maternal Deaths were caused by group A streptococcus [2] . Correspondingly, 50% of proven group A streptococcal infections in our study population led to septic shock, with very rapid progression from the first sign of SIRS. This has a direct implication for decisions about the availability of rapid antigen diagnostic tests for group A streptococcus in obstetrics. While culture remains the gold standard for confirmation of group A streptococcus, it takes 1–2 d to obtain results, which is significantly longer than the time course from the first signs of SIRS to septic shock for most women. In the absence of rapid diagnostics, a positive culture for group A streptococcus should be reported urgently by telephone as soon as it is discovered in the laboratory, and prior to this, a clinical suspicion of group A streptococcus should be regarded as a red flag for urgent action and very close monitoring. In addition, training about group A streptococcal infection should be routinely included in all obstetric emergency training courses.

In conclusion, this study emphasises that both primary and secondary care practitioners should remain aware that pregnant or recently pregnant women with suspected infection need closer attention than women who are not pregnant. Antibiotic prescription does not necessarily prevent progression to severe sepsis, and women should be followed up to ensure recovery. The rapid progression to severe sepsis highlights the importance of following the international Surviving Sepsis Campaign guideline of administration of high-dose intravenous antibiotics within 1 h of admission to hospital for anyone with suspected sepsis. Signs of severe sepsis, particularly with confirmed or suspected group A streptococcal infection, should be regarded as an obstetric emergency and should be routinely included in obstetric emergency training courses. Consideration could be given to a change of timing of prophylactic antibiotics to administration at time of decision for emergency cesarean section, and vigilant infection control at vaginal delivery should be maintained, with a potential role for prophylactic antibiotics at operative vaginal delivery. Future research should assess the efficacy of rapid antigen diagnostic tests for group A streptococcus in obstetrics.

Supporting Information

Checklist s1..

Strobe checklist.

https://doi.org/10.1371/journal.pmed.1001672.s001

Acknowledgments

The authors would like to thank the UKOSS reporting clinicians who notified cases and completed the data collection forms.

Author Contributions

Conceived and designed the experiments: CA JJK MK. Performed the experiments: CA MK. Analyzed the data: CA JJK DT MK. Wrote the first draft of the manuscript: CA. Contributed to the writing of the manuscript: CA JJK DNL DJT SS MK. ICMJE criteria for authorship read and met: CA JJK DNL DJT SS MK. Agree with manuscript results and conclusions: CA JJK DNL DJT SS MK.

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E-sepsis: early detection and treatment helping to save lives

Digital tools are making NHS staff’s working lives easier, improving patient care and the staff experience, helping them work more safely, more effectively and efficiently.

The reduction of mortality from sepsis, a serious and frequently occurring condition, across the NHS, is an example of how early recognition and treatment with digital tools can save lives.

E-Sepsis is a clinical decision support tool to increase screening for Sepsis and subsequent antibiotic administration.  E-Sepsis sees integration of a number of clinical parameters including patient observations and laboratory results. It automatically alerts clinicians when it detects a patient with sepsis. This removes the need for manual intervention and e-sepsis prompts clinical action by the clinical member of staff treating the patient. E-Sepsis ensures that screening for sepsis happens automatically, irrespective of ward, time of the day and clinician looking after the patient. Sepsis is monitored at individual, ward and Trust level – at any point in time, the Trust has an integrated view of the care of sepsis patients, and importantly are able to identify them as having sepsis much earlier and use this data to support improvement.

The tool has been developed in-house by the Trust’s digital team and works seamlessly with other systems in use by the Trust.

As a result of implementing the e-Sepsis decision support tool, in tandem with electronic observations and lab results, there are some remarkable improvements in managing Sepsis. These are:

• Screening for sepsis is consistently now at 100% for the Emergency Department (ED) and wards
• Antibiotic administration for patients with sepsis within 1 hour has increased to 90% in ED and 60% on wards.
• Mortality for sepsis has reduced from 23.17% to 22.92% 5%, severe septic shock mortality from 55.3% – 43.62%, severe sepsis mortality from 46.47% to 38.21%
• Septic shock mortality in under 45s has reduced from 60% to 7.69%

The above results to up to 200 lives saved through e-Obs, e-NEWS and e-Sepsis at Royal Liverpool and Broadgreen University Hospitals NHS Trust.

To access the Royal Liverpool and Broadgreen University Hospitals NHS Trust E-Sepsis blueprint, please email [email protected] .

Created by NHS Trusts, blueprints are step-by-step guides explaining how particular systems or innovations were developed and introduced and can be tailored to meet local requirements. They outline what’s needed to deliver the benefits of technology and lasting digital change e.g.; organisational leadership, technical guidance and clinical and staff engagement.

• Systematic Review
• Open access
• Published: 21 February 2024

Rapid systematic review on risks and outcomes of sepsis: the influence of risk factors associated with health inequalities

• Siân Bladon   ORCID: orcid.org/0000-0001-9087-6505 1 ,
• Diane Ashiru-Oredope 2 , 5 ,
• Neil Cunningham 2 ,
• Alexander Pate 1 ,
• Glen P Martin 1 ,
• Xiaomin Zhong 1 ,
• Ellie L Gilham 2 ,
• Colin S Brown 2 , 3 ,
• Mariyam Mirfenderesky 2 ,
• Victoria Palin 1 , 4 &
• Tjeerd P van Staa 1  

International Journal for Equity in Health volume  23 , Article number:  34 ( 2024 ) Cite this article

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Background and aims

Sepsis is a serious and life-threatening condition caused by a dysregulated immune response to an infection. Recent guidance issued in the UK gave recommendations around recognition and antibiotic treatment of sepsis, but did not consider factors relating to health inequalities. The aim of this study was to summarise the literature investigating associations between health inequalities and sepsis.

Searches were conducted in Embase for peer-reviewed articles published since 2010 that included sepsis in combination with one of the following five areas: socioeconomic status, race/ethnicity, community factors, medical needs and pregnancy/maternity.

Five searches identified 1,402 studies, with 50 unique studies included in the review after screening (13 sociodemographic, 14 race/ethnicity, 3 community, 3 care/medical needs and 20 pregnancy/maternity; 3 papers examined multiple health inequalities). Most of the studies were conducted in the USA (31/50), with only four studies using UK data (all pregnancy related). Socioeconomic factors associated with increased sepsis incidence included lower socioeconomic status, unemployment and lower education level, although findings were not consistent across studies. For ethnicity, mixed results were reported. Living in a medically underserved area or being resident in a nursing home increased risk of sepsis. Mortality rates after sepsis were found to be higher in people living in rural areas or in those discharged to skilled nursing facilities while associations with ethnicity were mixed. Complications during delivery, caesarean-section delivery, increased deprivation and black and other ethnic minority race were associated with post-partum sepsis.

There are clear correlations between sepsis morbidity and mortality and the presence of factors associated with health inequalities. To inform local guidance and drive public health measures, there is a need for studies conducted across more diverse setting and countries.

Introduction

Sepsis is “life-threatening organ dysfunction caused by a dysregulated host immune response to an infection” [ 1 ]. A 2015 study estimated the in-hospital mortality rate for sepsis in UK hospitals to be around 30% [ 2 ]. As well as high mortality rates, sepsis survivors often experience longer-term mental and physical health problems and are at high risk of post-discharge hospital readmission or death [ 3 , 4 , 5 ]. Risk factors for developing sepsis include frailty, immunocompromised status, recent surgical procedures, and comorbidities such as cancer, kidney disease, lung disease and diabetes [ 6 , 7 , 8 ]. The risk of contracting sepsis increases with age, with many sepsis cases occurring in people over the age of 65 [ 9 ]. Additionally, there is a higher risk of sepsis in neonates and women who are pregnant or have recently given birth.

Bacterial infections are the most common cause of sepsis and therefore antibiotics are widely used for treatment. A 2022 report published by the United Kingdom (UK) Academy of Medical Royal Colleges (AMRC) outlined recommendations for the recognition and early management of sepsis [ 10 ]. An aspect the report did not address, however, was the impact of health inequalities on sepsis recognition, management and outcomes. Inequalities can impact life expectancy, access to healthcare and general health status. Factors that are associated with these disparities include level of deprivation, ethnicity and belonging to more vulnerable groups within society, for example people experiencing homelessness [ 11 ]. In 2021, the National Healthcare Inequalities Programme was set up and developed the Core20PLUS5 approach, with the aim of supporting the National Health Service and local authorities in reducing health inequalities [ 11 ]. Core20 refers to populations living in the most deprived 20% of areas according to the Index of Multiple Deprivation (IMD). PLUS refers to population groups identified at local level that could include ethnic minority groups, coastal communities, populations defined as having a protected characteristic under the Equality Act 2010 or belonging to an inclusion health group, amongst others. ‘5’ refers to five clinical areas of importance, which are maternity, severe mental illness, chronic respiratory disease, early cancer diagnosis, and hypertension case-finding.

Variations in rates of antimicrobial resistant infections and microorganisms (associated with higher mortality rates in sepsis [ 12 ]) have been reported in the UK amongst different ethnic groups and levels of deprivation [ 13 ]. A recent study reported increased odds of non-COVID 19 related sepsis and increased mortality in more socioeconomically deprived people during the pandemic [ 14 ]. In the face of increasing resistance to antimicrobials globally, knowing who is at greatest risk of developing sepsis may not only improve patient outcomes but help target the use of antimicrobials more effectively.

A 2019 systematic review assessed the link between race and socioeconomic status and sepsis outcomes. However, they only included studies conducted in the USA [ 15 ]. The purpose of this review, therefore, was to identify studies from all high- income countries that have assessed additional factors associated with health inequality. The aims of this rapid review were (i) to summarise the literature that investigated health inequalities and sepsis incidence and mortality outcome and (ii) to provide an evidence base for public health advice to reduce the impact of health inequalities with sepsis.

Eligibility criteria

Peer-reviewed journal articles published between 01/01/2010 and 31/01/2023, written in English, were eligible for inclusion. Included studies had to be observational in design where the main outcome was either incidence or risk of sepsis (in the general population or hospital admissions) or sepsis-associated mortality. We included studies where the aim was assessing the impact of one of the following health inequality factors: socioeconomic, race/ethnicity, community, medical vulnerability, or pregnancy. Studies were excluded if they were conducted in a low- or middle-income country (LMIC) (according to the World Bank, to minimise differences in healthcare systems), were not observational in design (intervention studies or qualitative studies), full text was not available, or abstract was published in conference proceedings.

Study selection

The database Embase (accessed through Ovid, last searched 25/03/3023) was used to search for relevant articles. Separate searches were carried out using the following terms in the titles of articles: sepsis OR septic in combination with one of the following groups of terms:

Socioeconomic factors – depriv* or socioeconomic or socio-economic or socio or social or SES or IMD or income or occupation or education.

Race/ethnicity factors – race or racial or ethnic* or minorit*.

Community factors – urban* or rural or coast*.

Medical vulnerability factors – residen* or care home or nursing home or care facility or living or social care or drug* or alcohol or disabil* or vulnerab*.

Pregnancy – pregnan* or matern* or “post-partum” or “postpartum”.

Duplicated articles were removed. All articles identified in the search went through a title and abstract screening to exclude ineligible articles. A full article review was then performed on the remaining papers, with any ineligible articles identified during the full paper review being excluded. In accordance with the PRISMA guidelines, the reasons for exclusion at this stage were recorded (see Fig.  1 ). Any further duplicates (studies that appeared in multiple searches) were also removed. The searches were performed in Ovid and the results were downloaded to Mendeley Reference Manager to apply the inclusion/exclusion criteria. Data extracted from the eligible articles were stored in Microsoft Excel. The following information was extracted from each included paper: title, authors, year published, study design, country where study was conducted, data source, sepsis identification method, number of patients in sepsis cohort, factors associated with inequality used in study and how they are measured, outcome(s) assessed in the study and key findings of associations between the factors and outcomes. For reporting we referred to the PRISMA guidelines [ 16 ] for systematic reviews, however, as this is a rapid review not all items are relevant. Further details of the search strategy can be found in the supplementary information.

Selection of sources of evidence

The five searches returned a total of 1,402 results (185 socioeconomic, 92 race/ethnicity, 126 community, 494 medical/care needs, 505 pregnancy). After deleting duplicates, 1,338 papers were screened on title and abstract, with 1,254 excluded. 108 papers underwent full article screening, after which 53 were eligible. Of these, there were 13 articles assessing socioeconomic factors, 14 race or ethnicity, 3 assessing community, 3 care/medical needs, and 20 assessing pregnancy and post-partum factors. As the searches and selection were conducted separately there were 3 papers duplicated between the searches, resulting in 50 unique papers to include. Flowcharts showing the selection process for each search are shown in Fig.  1 .

Flowchart showing search results and screening of studies. Five separate searches were conducted. After screening 53 papers were included

Characteristics of sources of evidence

Table  1 displays the characteristics of studies included in the review. The majority of the included studies (31 out of 50) used data collected in the United States of America (USA) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ], with four in the UK [ 48 , 49 , 50 , 51 ], three in Israel [ 41 , 52 , 53 ], two in Canada [ 54 , 55 ], one in Australia [ 56 ] and the others in Europe [ 57 , 58 , 59 , 60 , 61 , 62 , 63 ] or not specified [ 64 , 65 ].Most of the studies used hospital or ICU discharge databases [ 17 , 21 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 47 , 50 , 60 ], other sources included national birth or obstetric registries [ 48 , 49 , 51 , 62 , 63 ], death registry datasets [ 27 , 35 ], secondary analysis on data collected for other cohort studies [ 18 , 26 , 61 ], and a US cities public health dataset [ 22 ]. Six identified sepsis in neonatal patients or infants [ 21 , 47 , 53 , 55 , 56 , 63 ] and another only included children aged between 0 and 20 years [ 28 ]. The rest either specified adults only or did not specify any age restrictions for the cohorts.

The most common method of identifying sepsis in the studies was based on ICD codes. ICD-10 codes were used in twelve studies [ 17 , 20 , 27 , 28 , 32 , 40 , 46 , 54 , 60 , 61 , 62 , 63 ], ICD-9 codes were used in twenty-one studies [ 20 , 21 , 24 , 25 , 29 , 31 , 32 , 33 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 45 , 46 , 52 , 61 , 65 ] and one study did not specify which ICD version [ 34 ]. Of these studies, some used specific codes for sepsis, severe sepsis or septic shock whilst others used more comprehensive sets of codes including the Angus criteria [ 66 ] or Martin criteria [ 67 ]. Both the Angus and Martin methods include the sepsis specific codes and non-specific ICD codes for infection in combination with a code for organ dysfunction. Five studies [ 18 , 19 , 22 , 23 , 30 ] used the 2016 International Consensus definition for sepsis, otherwise known as the Sepsis-3 criteria [ 1 ]. Other studies used Systemic Inflammatory Response Syndrome with [ 50 ] and without criteria for organ dysfunction [ 26 , 64 ], medical chart review [ 48 , 49 , 51 , 53 , 55 , 56 , 59 ] or did not specify [ 22 , 35 , 47 , 57 , 58 ]. The size of the sepsis patient cohorts varied from 14 [ 56 ] to 16,779,820 [[ 33 ] with a median cohort size of 2,913.

Regarding outcomes, 15 studies assessed the incidence or risk of sepsis [ 18 , 26 , 29 , 31 , 37 , 41 , 42 , 48 , 49 , 50 , 54 , 57 , 59 , 60 , 61 , 62 ], 23 studies looked at in-hospital (or short-term) mortality [ 17 , 19 , 20 , 21 , 24 , 25 , 28 , 31 , 33 , 34 , 36 , 37 , 39 , 43 , 44 , 45 , 50 , 51 , 52 , 54 , 58 , 59 , 65 ], four studies assessed mortality after hospital discharge [ 30 , 32 , 38 , 58 ], five studies assessed hospital readmission rates after discharge [ 23 , 30 , 32 , 40 , 58 ] and four studies calculated population-level sepsis mortality rates [ 22 , 27 , 35 , 61 ]. Seven of the studies relating to pregnancy assessed adverse perinatal outcomes and incidence of sepsis in neonates [ 46 , 47 , 53 , 55 , 56 , 63 , 64 ].

Results of individual sources of evidence

Socioeconomic factors.

The most common socioeconomic factors were income, level of education, employment status, unemployment rate and poverty rate. Others included were insurance status, occupation, cohabitation status and access to healthcare. There was variation in whether these were recorded at an individual level or matched to local data based on small area geographic identifiers (ZIP/postcode), and whether they were summarised into an overall score or included as individual covariates.

Five studies assessed the impact of socioeconomic factors on sepsis incidence or risk of developing sepsis. Factors found to be associated with increased risk of sepsis included low income [ 54 , 60 ], low education level [ 57 , 60 , 61 ], lower socioeconomic status [ 18 ], marital/living status [ 54 , 57 ] not being in work [ 54 , 57 ], lower class of occupation and those who receive social benefits [ 61 ]. Three studies assessed 30-day or in-hospital mortality, which all found lower income was associated with increased risk of mortality when compared to the highest income groups. Another study reported decreased odds for highest household income quartile compared to the lowest quartile [ 20 ]. Hidalgo et al. [ 19 ] reported that unemployment and a neighbourhood poverty rate > 10% were all predictive of greater 30-day mortality. One study calculated population sepsis mortality rates per 10,000 persons and compared between income and poverty levels. Low-income neighbourhoods had a death rate of 3.65 (inter-quartile range (IQR) 2.78–4.40) versus high income neighbourhoods 2.80 (IQR 2.05–3.55) and high poverty neighbourhoods 4.20 (IQR 2.90–5.30) versus low poverty neighbourhoods 2.90 (IQR 2.00-3.60) [ 22 ]. For longer-term outcomes, two studies assessed the impact of socioeconomic factors on 30-day readmission after discharge. Lower income, lack of health insurance [ 23 ] and being more socioeconomically disadvantaged [ 23 ] were found to be associated with increased risk.

Race & ethnicity

Of the 14 studies assessing the impact of race or ethnicity on sepsis, 13 were based in the USA. Five of these studies only included race categorised as white or black/African-American [ 25 , 26 , 29 , 31 , 32 ], whilst other studies included categories for Hispanic [ 21 , 24 , 27 , 28 , 33 , 34 ], Asian-American [ 24 , 30 ], Asian/Pacific Islander (API) or Native American [ 21 , 28 , 33 ] and other/unknown. The study by Rush et al. [ 34 ] used a different approach by classifying hospitals as non-minority or minority, if the patient population of the hospital was more than twice the geographical census division mean.

The studies by Chaudhary et al. [ 31 ], Mayr et al. [ 29 ] and Moore et al. [ 26 ] compared rates of sepsis amongst either black or white populations only. Chaudhary et al. reported a higher sepsis rate for white patients compared to black patients with 109.4 cases (95% CI 109.2-109.6) per 1,000 hospitalisations versus 106.7 cases (95% CI 106.3-107.1). Moore et al. also reported a higher incidence of sepsis in white patients (9.10 per 1,000 person years) compared to black patients (6.93 per 1,000 person years). Contrary to these, Mayr et al. found a 67% higher severe sepsis hospitalisation rate in black patients (9.4 per 1,000 population) than white (5.6 per 1,000 population). All three studies covered hospital admissions in multiple US states, but they did differ in the age of patients included and severity of sepsis.

Eight studies considered the impact of race on in-hospital mortality in sepsis patients, with mixed results. Three studies reported higher mortality rates or increased risk of mortality in black or African-American patients than white patients [ 25 , 28 , 33 ] whilst Sandoval et al. [ 24 ] reported higher case fatality rates in white patients (15.1%) compared to black (14.0%), Hispanic (13.8%) or Asian patients (16.2%). One study [ 33 ] reported increased mortality rates in Hispanic patients compared to white patients, but two other studies did not find significant differences [ 21 , 28 ]. Rush et al. reported unadjusted mortality rates at non-minority hospitals of 11.1%, compared with 12.3% ( p  < 0.001) at minority black hospitals and 12.7% ( p  < 0.001) at minority Hispanic hospitals. The only non-USA based study was based in Israel. Karp et al. [ 52 ] found that differences in risk of in-hospital mortality between Bedouin Arabs and the Jewish population could be explained by differences in age and Charlson comorbidity score.

For longer-term outcomes, one study [ 30 ] reported small differences in 90-day mortality rates between African American (18%), Asian-American (19%) and white (22%) patients. Lizza et al. [ 32 ] reported black patients had significantly higher rates of all-cause readmission (71.1% vs. 60.8%, p  < 0.001) and sepsis readmission (19.8% vs. 14.0%, p  < 0.001) than white patients. However, rates of post-discharge death were similar (white patients 36.5% vs. black patients 36.7%, p  = 0.876). Ogundipe et al. [ 27 ] calculated age-adjusted sepsis death rates in non-Hispanic black, non-Hispanic white and Hispanic populations and reported lower death rates in Hispanic populations than non-Hispanic populations.

Community factors

The three papers included in the review that looked at community factors were conducted in the USA and used different ways of measuring urbanicity or rurality. Oud et al. [ 35 ] compared age-adjusted sepsis mortality rates between rural and urban communities from 2010 to 2019. The study reported in 2019 the overall rural rate was 57.9 deaths per 100,000, but in urban areas it was 48.3 deaths per 100,000 population. This was not a consistent pattern when adjusting for race. For example, in non-Hispanic blacks the urban mortality rates were higher than the rural rates. Ogundipe et al. [ 27 ] found the highest age-adjusted sepsis death rates were in non-metropolitan areas for both non-Hispanic black (micropolitan area 120.4 per 100,000 population, non-core area 109.4 per 100,000) and non-Hispanic white populations (micropolitan area 67.6 per 100,000, non-core area 66.4 per 100,000). Mohr et al. [ 36 ] assessed whether there were differences in patients in rural areas who attended their local emergency department or who bypassed their local hospital and travelled further to present to a hospital of top-decile inpatient sepsis volume. Sepsis patients who bypassed their local hospital had increased odds of mortality, with an OR of 1.26 (95% CI 1.03–1.53).

Medical needs

The three studies that considered factors relating to additional medical needs each used different measures. Goodwin et al. [ 37 ] identified patients living in medically underserved areas (MUA’s) based on the ratio of primary care physicians per 1,000 population, infant mortality rate, the proportion of the population with income below the poverty level and the proportion of the population over 65 years of age. The study reported higher incidence of sepsis (8.6 vs. 6.8 admissions per 1,000 people, p  < 0.01) and mortality rates (15.5 versus 11.9 deaths per 10,000, p  < 0.01) in MUA residents compared to non-MUA. Ginde et al. [ 39 ] included residence in a nursing home prior to an emergency department visit for sepsis, and reported increased risk of mortality for nursing home residents (OR 3.1, 95% CI 1.2–7.8). The study by Ehlenbach et al. [ 38 ] found that sepsis patients not discharged to a skilled nursing facility (SNF) had a mortality rate of 35.6%, while those discharged to a SNF but whom had not been resident in an SNF prior to sepsis had a mortality rate of 43.2% and patients who had been in a SNF before and after sepsis had a mortality rate of 52.8%.

Pregnancy/maternity

Studies assessing incidence of maternal sepsis reported rates of severe sepsis of 1.00 per 100,000 [ 48 ] maternities, 4.7 per 10,000 [ 49 ] maternities and 4.9 per 10,000 live births [ 42 ]. Estimates of non-severe sepsis included 198.69 per 100,000 [ 59 ] maternities, 2.4 per 10,000 women [ 62 ] and 10 per 10,000 live births [ 42 ]. Acosta et al. [ 50 ] estimated the absolute risk of maternal critical care unit admission with severe sepsis was 4.1 per 10,000 maternities (95% CI 2.9–5.6). Factors including increased BMI [ 41 , 50 , 62 ], older age [ 42 , 50 , 62 ], black and other ethnic minority race [ 49 ], increased levels of deprivation [ 50 ], African American race [ 41 ], pre-existing medical conditions [ 41 , 49 ], complications of delivery and delivery via caesarean Sects [ 41 , 49 , 50 , 59 , 62 ] were found to be associated with an increased risk of developing maternal sepsis.

Two studies [ 43 , 44 ] assessing mortality in maternity patients reported lower case-fatality rates in pregnancy associated severe sepsis (PASS) compared to non-pregnancy associated severe sepsis (NPSS). Maternal mortality rates in other studies varied, with reported rates of 10% [ 65 ], 10.7% [ 51 ], 1.8/100,000 maternities [ 50 ] and no deaths in one study [ 59 ]. Increased BMI [ 50 ], being in the most deprived two IMD quintiles [ 50 ], pre-existing medical conditions [ 51 ] and being multi-parous [ 51 ] was found to be associated with increased maternal mortality. Antepartum sepsis was found to be associated with increased risk of placental dysfunction and maternal ICU admission during delivery hospitalization [ 46 ]. Five studies considered outcomes relating to early onset neonatal sepsis (EONS), with reported rates of 1.03 cases per 1,000 live births [ 53 ] and 1.48 per 1,000 live births [ 63 ]. Risk factors associated with EONS were maternal exposure to antibiotics [ 47 , 53 , 55 ], maternal BMI [ 63 ], caesarean section delivery [ 63 ] and gestational age [ 47 ].

Supplementary Tables 1 and 2 show the findings from all included studies and can be found in additional file 1.

Summary of evidence

Socioeconomic factors associated with increased incidence of sepsis included lower socioeconomic status, unemployment, and lower education level, although findings were not consistent across studies. Studies assessing the association between ethnicity and sepsis rates reported mixed results, with two studies finding increased sepsis rates in white populations compared to black populations and another showing higher rates in black populations than white. Living in a medically underserved area or being resident in a nursing home was also shown to increase risk of sepsis. In terms of mortality, lower income, unemployment, and poverty levels were all associated with increased in-hospital mortality. In studies considering effects of ethnicity on in-hospital and longer-term mortality the results were mixed, with some studies finding no significant associations, some reporting increased odds of mortality in non-white populations and others reporting increased mortality in white populations. Sepsis mortality rates were also found to be higher in people living in rural areas and those who were resident in a skilled nursing facility.

It is notable that the literature is dominated by research conducted in the USA and none of the studies identified under the non-pregnancy related searches used UK data. This is an important consideration for healthcare and public health professionals outside of the USA as differences in structural inequalities between the USA and other high-income countries may make the results less generalisable. The majority of studies focused on in-hospital mortality as the primary outcome, so there also needs to be more focus on the risks of developing sepsis and longer-term outcomes such as healthcare utilisation.

The sources of data varied between the studies, as did the methods of identifying sepsis. Differences in sepsis definitions leads to different reported prevalence/cohort sizes [ 68 ]. Some of the studies were based in single centres and only included a few hundred patients, whilst others represented national populations and included millions of patients. Many of the studies used data from secondary care only and none used primary care data, even though the majority of cases of sepsis develop in the community rather than the hospital. Additionally, there was a lot of variation in measures used in the analyses, particularly in the studies assessing socioeconomic factors, where there was no standardised definition of socioeconomic status and therefore results varied. There were some studies who assessed a combination of socioeconomic, community and race factors, however, some only focused on one area related to health inequality. This is important as there is overlap between the different areas. The paper by Vazquez Guillamet et al. [ 20 ] concluded that race did not have a significant effect on sepsis mortality when accounting for socioeconomic variables. A commentary piece published in 2018 by Shankar-Hari and Rubenfeld [ 69 ] titled “Race, ethnicity and sepsis: beyond adjusted odds ratios” suggested that there needs to be more research into the underlying causes of race/ethnicity disparities not just in sepsis but in wider health areas. Future studies should take into account not just socioeconomic status and population demographics, which will likely vary between ethnic groups, but also consider the intersectionality between these and other factors such as comorbidity levels and health behaviours e.g. smoking, alcohol use or exercise.

Limitations

Due to the rapid nature of the review the scope was limited and the search strategy not as comprehensive as for systematic reviews. We searched for the key terms in the titles only, searched a single database (Embase) and only included studies published from 2010 onwards. We also acknowledge that pathogen specific publications which do not specifically include the word sepsis may have been screened out. Examples include those that report on invasive group A and B streptococcal disease [ 67 ]. Studies conducted in LMICs were excluded as the results will be less generalisable to the UK population. Whilst the burden of sepsis is highest in LMICs there is a lack of good quality data from these countries [ 70 ]. The challenges in recognising and managing sepsis within LMICs, such as lack of access to healthcare, malnutrition and infrastructure [ 71 ], are not as applicable in higher- income countries. Some aspects of the Core20PLUS5 approach to addressing health inequalities were not included in this rapid review. These mainly related to inclusion health groups, including people with multi-morbidities, vulnerable migrants, Gypsy, Roma and Traveller communities, sex workers, people in contact with the justice system and victims of modern slavery. Additionally, the 4 comorbidities/conditions within the ‘5’ component other than maternity were not areas of focus (severe mental illness, COPD, cancer & hypertension). The five included areas were chosen as they are the factors that cover the largest groups in the population and were identified as the most important. Although we did not include the other areas in our review it is still vital that future studies consider these aspects in order to address all potential influences on sepsis risks and outcomes. The bias of the included studies was not assessed, nor did we critically appraise them.

Future work

From the studies identified, there are clear correlations between sepsis morbidity and mortality and the presence of factors associated with health inequalities. There is a need for UK based studies, using nationally representative data, to better understand how factors associated with health inequalities affect sepsis incidence and mortality in the UK population. With the availability of electronic health record data for research there are increasing opportunities to disaggregate the data and stratify risk by patient demographic. For example, in the UK the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data provide nationally representative primary and secondary care records with linkage available to deprivation and socioeconomic scores. Once this is better understood, healthcare and public health professionals can be empowered to close the health gap and reduce inequalities through targeted recommendations for the recognition and early management of sepsis. Recent guidance in the UK highlighted the importance of early intervention in sepsis whilst balancing that with the need to use antibiotics more appropriately. Understanding which patients are at greater risk of sepsis mortality and morbidity, in terms of the factors associated with inequalities discussed in this review and other known risk factors, may help clinicians target antibiotic use more effectively. Given the lack of evidence from outside the USA, there is not sufficient information available to inform policy, at either a global level or an individual country level (except the USA). Although some of the findings from USA studies may be generalisable to other settings there needs to be further exploration of the similarities and differences in inequality factors in different populations. Critical to the above is improved coding in electronic health records alongside appropriate data linkage.

Factors relating to health inequalities such as deprivation and ethnicity have been shown to be associated with poorer outcomes in COVID-19 and increased rates of antimicrobial resistance. In order to inform local guidance and drive public health measures, there is a need for studies conducted across more diverse setting and countries.

Data availability

All data generated or analysed during this study are included in this published article and supplementary materials.

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D.A.O., N.C., M.M., C.B, and E.G. devised the study. D.A.O., N.C., E.G., T.vS, S.B., X.Z, V.P., A.P., G.M. and S.B. devised search terms and inclusion/exclusion criteria. S.B. conducted the searches, extracted the data and wrote the manuscript. All authors reviewed and edited the manuscript.

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Additional file 1: Table 1

. Findings of studies assessing the impact of factors of health inequality on sepsis incidence or risk. Table 2 . Findings of studies assessing the impact of factors of health inequality on sepsis mortality and other outcomes.

Additional file 2

. Search strategy including PICO criteria and exact search terms.

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Bladon, S., Ashiru-Oredope, D., Cunningham, N. et al. Rapid systematic review on risks and outcomes of sepsis: the influence of risk factors associated with health inequalities. Int J Equity Health 23 , 34 (2024). https://doi.org/10.1186/s12939-024-02114-6

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Recognition and management of neonatal sepsis

Luke William Crocker

5th Year Medical Student, University of Bristol, Bristol

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Ayesha White

Paul Anthony Heaton

Consultant Paediatricians, Yeovil District Hospital

Débora Pascoal Horta

Ward Manager, Special Care Baby Unit, Yeovil District Hospital, Yeovil

Siba Prosad Paul

Consultant Paediatrician, Torbay Hospital, Torquay

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Neonatal sepsis results from acute bacterial or viral infection occurring in the first 28 days of life. It causes significant morbidity and mortality, although the outcome can be improved by early recognition and prompt treatment by health professionals. This article describes the most common causes of sepsis, and explains why neonates are particularly vulnerable to infection. It highlights the non-specific way in which an infant with a serious infection may present, indicating the crucial features to elicit during history taking and examination, and emphasising the ‘red-flag’ signs and symptoms that should increase suspicion of a serious illness. The authors have adapted National Institute for Health and Care Excellence guidelines to produce an evidence-based approach to the management of an infant with suspected sepsis, and describe the roles of nurses in ensuring effective treatment and best outcomes for these babies.

Neonatal sepsis occurs when there is a serious bacterial or viral infection manifesting in the first 28 days of life (National Institute for Health and Care Excellence ( NICE) 2012 ). A systematic review with meta-analysis by Fleischmann-Struzek et al (2018) involving 23 studies estimated that it carries a mortality rate of 11–19*. The same study estimated that, globally, 3 million neonates are affected each year; the non-specific and varied nature of presentation may result in late diagnosis and delayed treatment. It is important that health professionals are aware of the condition and suspect sepsis at an early stage. This article details the clinical features of neonatal sepsis and includes two illustrative case studies to provide context.

Epidemiology

Neonatal infections are divided into early-onset sepsis (EOS) occurring within the first 48 hours of birth, and late-onset sepsis (LOS) occurring between 2 and 28 days after birth ( Cailes et al, 2018 ). The neonatal infection surveillance network (NeonIN) study involving 12 neonatal units in England over a 10-year period recorded a total of 541 bacterial infections in 443 infants; it recorded an infection rate of 8/1000 live births, and 71/1000 in those admitted to the neonatal unit; sepsis was most common among male infants (56*) born prematurely (<37 weeks) and/or had a low birth weight <2500 g ( Vergnano et al, 2011 ).

In another UK study, the incidence of EOS was 0.9/1000 live births and 9/1000 neonatal admissions; the majority (76*) of cases were diagnosed on the first day of life ( Cailes et al, 2018 ). EOS had a weak association with gestational age and birth weight. Infants were premature in 58* of EOS cases, and 50* had a low birth weight (weighing <2.50 kg). Most EOS cases in the UK are caused by Gram-positive organisms (74*), notably group B Streptococcus (GBS); Gram-negative organisms account for 25* of cases and Candida 1*. Bacteria causing neonatal sepsis are usually found in the maternal genital tract; GBS and Escherichia coli account for around 70* of EOS infections, but other causative organisms should always be considered ( Simonsen et al, 2014 ).

In a study by Vergnano et al (2011) , LOS was more common than EOS, with an incidence of 7/1000 live births, and accounting for 61/1000 neonatal admissions. LOS occurred at a median age of 20 days and had a stronger correlation with prematurity; 92* of cases occurred in those born at <32 weeks and 90* of cases had a low birth weight (<2500 g) ( Vergnano et al, 2011 ). Coagulase negative Staphylococci (CoNS) was regarded as a pathogen only if there were central lines in situ or if the neonate was very unwell and CoNS was the only organism cultured; it is mostly associated with prematurity. Bacterial growth identified in LOS were Gram-positive in 49* of cases and Gram-negative organisms in 42* fungi were responsible for the remaining 9* ( Vergnano et al, 2011 ).

A prospective cohort study conducted in Northern Ireland involving 93 episodes of LOS in 61 babies found a 13* incidence of human parechovirus infection, and 54.4* of these tested positive for a concomitant bacterial infection ( Davis et al, 2015 ). These findings reiterate the importance of awareness that neonatal sepsis may be caused not only by bacteria, and that viral causes should also be considered. A negative bacterial culture does not eliminate the possibility of sepsis.

Pathophysiology

In bacterial or viral infection the innate immune system is the first line of protection and mounts an immune response involving the release of a wide range of inflammatory mediators that possess anti-infective qualities ( Wynn and Levy, 2010 ). These mediators include tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), all of which are all pro-inflammatory cytokines released in response to infection ( Machado et al, 2014 ). These inflammatory mediators promote activation of immune cells, leading to the release of polymorphonuclear leukocytes, histiocytes, platelets and endothelial cells ( Bayston and Cohen, 1990 ). This in turn results in a cascade that produces more pro-inflammatory mediators such as platelet-activating factor (PAF), arachidonic acid metabolites and histamine. Severe sepsis in neonates can be defined by the presence of these pro-inflammatory cytokines beyond the third day following diagnosis. The complex pathogenesis and imbalance, in neonatal sepsis, of interactions between pro-inflammatory and anti-inflammatory mediators is still not fully understood ( Machado et al, 2014 ).

Neonates are highly susceptible to infection due to their poorly developed skin barrier and generally immature immune system ( Satar and Özlü, 2012 ). Babies born before 30 weeks' gestation are particularly at risk because transfer of maternal antibodies mostly occur after this time. Decreased levels of complement protein and reduced monocyte function further compromise innate immunity, resulting in reduced ability to produce pro-inflammatory cytokines. These factors result in increased susceptibility, incidence and severity of infection in the newborn ( Satar and Özlü, 2012 ).

Risk factors

The various risk factors associated with EOS and LOS are presented in Box 1 and Box 2 . Premature birth, low birth weight and suspected/confirmed maternal sepsis carry a particularly high risk for neonatal sepsis. Mothers with a history of confirmed GBS on high vaginal swabs in the current or a previous pregnancy should be offered antibiotic prophylaxis during labour.

Box 1.Risk factors for early-onset sepsis

• Invasive group B streptococcal infection in a previous sibling in the neonatal period
• Maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy
• Prelabour rupture of membranes
• Preterm birth following spontaneous labour (<37 weeks' gestation)
• Suspected or confirmed rupture of membranes for >18 hours in a preterm birth
• Intrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis
• Parenteral antibiotic treatment given to the pregnant woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth [This does not refer to intrapartum antibiotic prophylaxis]
• Suspected or confirmed infection in another baby in the case of a multiple pregnancy

Source: adapted from National Institute for Health and Care Excellence, 2012

Box 2.Risk factors for late-onset sepsis

• Low birth weight
• Prematurity
• Long-term use of invasive interventions (for example, mechanical ventilation, indwelling catheters and central lines)
• Need for parenteral nutrition
• Absence of breastfeeding
• Prolonged period of hospitalisation
• Previous surgery
• Underlying respiratory or cardiovascular diseases
• Prolonged period of nil by mouth
• Low Apgar score
• Maternal exposure to antibiotics

Sources: National Institute for Health and Care Excellence, 2012; Simonsen et al, 2014; Fenton-Jones et al, 2017

Differential diagnoses

The three main diagnoses to consider in an acutely unwell neonate are sepsis, congenital heart disease and metabolic disorders. Other less likely diagnoses include, but are not limited to, acute surgical diagnoses, seizures, endocrine crises, enteric emergencies and trauma. Table 1 outlines the differential diagnoses to consider in an infant presenting with suspected sepsis.

The neonate presenting with suspected sepsis needs consideration of a number of different aspects including maternal history and perinatal history (included in risk factors for EOS and LOS and red flags, Box 3 ). We have suggested below a framework for health professionals to consider when obtaining a history of the baby's presentation ( NICE, 2012 ; Fenton-Jones et al, 2017 ); most of these would be relevant in LOS, but would be useful to ask in neonates whose parents may have chosen to take an early discharge from the hospital and subsequently presented to the emergency department (ED):

• Gestational age and birth weight
• Method of delivery: normal delivery, instrumental or Caesarean section
• How long has the infant being unwell and what is his or her response to handling?
• Has there been any reduction/change in activity levels, eg sleepy, drowsy, irritability?
• Duration of rupture of membranes (if >18 hours increased risk of infection)
• Any reduction in fluid intake (and reduced urine output—important markers of dehydration)
• Any abnormality detected during the newborn and infant physical examination (NIPE) ( Public Health England, 2013 ) screening results (in LOS)
• Any symptoms of breathing difficulties, heart racing, vomiting, diarrhoea, abdominal distension, fever, bulging fontanelle (examined with the neonate held in sitting position), appearing pale or mottled etc
• Whether a previous sibling has been affected by GBS sepsis.

Box 3.Red flags: aspects of symptoms to consider in a neonate presenting with suspected sepsis

• Respiratory distress starting >4 hours after birth
• Jaundice <24 hours of life
• Need for mechanical ventilation in a term baby
• Signs of shock
• Other risk factors for early-onset/late-onset sepsis
• Vomiting, excessive gastric aspirates and abdominal distension
• Local signs of infection (for example, affecting the skin or eye)
• Hypothermia (<36°C) or pyrexia (>38°C) which is non-environmental in origin

Sources: National Institute for Health and Care Excellence, 2012; Fenton-Jones et al, 2017

Examination

The features of sepsis, particularly in a neonate, are often non-specific ( Fenton-Jones et al, 2017 ). Baseline observations should include: respiratory rate, heart rate, saturations, temperature, central capillary refill time and an AVPU (alert, voice response, pain response, unresponsive) score; these should be recorded for every infant. These observations should be plotted on a neonatal early warning score (NEWS) because neonates have specific reference ranges that will be different from those for adults and children. Paediatric early warning scores (PEWS) may be used because the neonate may be cared for in settings other than neonatal units or when presenting to the ED with LOS. It may be useful to consider some red flags while assessing the neonate as highlighted in Box 3 .

Nurses working in an advanced neonatal nurse practitioner (ANNP) or enhanced neonatal nurse practitioner role may be expected to perform a neonatal examination, observing and recording skin colour, activity, response to handling, wakefulness and tone, and monitoring the baby's condition.

The absence of a fever does not rule out the possibility of sepsis because many neonates, especially those born prematurely, may not become pyrexial in response to an infection, a reflection of the immature function of the newborn physiology. An analytical study from Pakistan looking at culture-proven and probable neonatal sepsis cases admitted to the neonatal intensive care unit found that 28.9* of neonates had mild or moderate hypothermia, while 13.1* had hyperthermia ( Ahmad et al, 2016 ). Likewise, photophobia and neck stiffness are frequently not elicited in neonates with confirmed meningitis; instead, they may show non-specific signs such as poor feeding, intolerance to handling, covering their eyes by moving their forearm and arching of their back ( NICE, 2012 ; 2016 ).

Investigations

Once the clinical suspicion of EOS/LOS has been raised, a set of essential investigations, including a blood culture, should be carried out before administering antibiotics. Table 2 shows a list of investigations to consider. Special investigations such as cranial ultrasound scans and lumbar punctures may need to be delayed until the baby is stable.

CSF=cerebrospinal fluid; EOS=early-onset sepsis; LOS=late-onset sepsis

If the infant belongs to a high-risk group or suspicion is high, antibiotics should be started without delay and specialist investigations may need to be carried out afterwards ( NICE, 2012 ).

Infants can present very unwell with sepsis, potentially even in a state of shock. The multidisciplinary team should initiate an ABCDE (airway, breathing, circulation, disability and exposure) approach to achieve stable status. The administration of appropriate antibiotics should remain a priority, ideally administering them within 1 hour from presentation to the hospital.

Antibiotic therapy

For EOS, NICE (2012) advises the administration of an empirical antibiotic combination of intravenous benzylpenicillin and gentamicin. The dose and duration of gentamicin administration may vary depending on hospital policy. A UK-wide survey by Fernando et al (2008) , and preceding the publication of the NICE Clinical Guideline 149 (2012), found that only 69* of neonatal units were following the above antibiotic regimen for EOS.

The NICE guideline states that the need for continuation of antibiotic therapy for suspected EOS should be reviewed at 36 hours and then discontinued if the following criteria are fulfilled ( NICE, 2012 ):

• Blood culture remains negative
• Neonate remains clinically well
• C-reactive protein (CRP) levels and trends remain reassuring
• Initial suspicion of EOS was low.

For LOS, NICE (2016) suggests using cefotaxime, with amoxicillin cover for Listeria. The length of antibiotic therapy will depend on the nature of the bacterial growth identified and site of infection. This should be decided through a joint consultation between the paediatrician and microbiologist ( NICE, 2012 ; 2016 ).

Antiviral therapy

Herpes and varicella zoster infections are usually treated with antiviral agents. Acyclovir is the antiviral of choice for herpes virus infections, with the length of the therapy based on the clinical information. Infants whose mothers develop chickenpox (varicella zoster) between 7 days pre-delivery and 7 days post-delivery should be given varicella zoster immunoglobulin (VZIG) as prophylaxis. This can be given without testing the infant for antibodies ( Public Health England, 2019 ).

Antipyretic therapy

Paracetamol is used to reduce distress and improve hydration and is dosed according to body weight, with doses varying dependent on the corrected gestational age. Ibuprofen is not recommended in infants with a body weight below 5 kg or aged <3 months ( Joint Formulary Committee, 2021 ).

Intravenous fluid support

Fluid resuscitation for neonates should be with 0.9* normal saline, with a bolus of 10 mL/kg given over 10 minutes. A second bolus may be given if there is no improvement ( NICE, 2016 ).

Oxygen support

Oxygen should be administered in cases of suspected sepsis when there are signs of shock or oxygen saturation of less than 92* when breathing on room air ( NICE, 2016 ).

Neonates should be monitored using a NEWS or modified PEWS scoring system, with repeated assessments 2 to 4 hourly. Strict input/output monitoring of fluids is essential ( Roland, 2012 ; Fenton-Jones et al, 2017 ). A change in score on a NEWS/PEWS scoring system should initiate a medical reassessment.

Role of nurses

Prognosis and outcomes of children presenting with EOS/LOS depends on the cause and the site of infection, eg sepsis, meningitis, urinary tract infection, pneumonia, or a combination of these conditions. However, early recognition and escalation to senior clinicians is likely to make a difference to prognosis and long-term outcomes. It is imperative that nurses remain aware of the common, as well as often non-specific presentations of EOS/LOS, and be familiar with the need for time-critical management. An overview of the different roles of nurses who may encounter children with EOS/LOS is presented in Table 3 .

EOS=early-onset sepsis; HDU=high-dependency unit; LOS=late-onset sepsis; NEWS/PEWS=neonatal/paediatric early warning score

Case report

Case 1. early-onset sepsis.

A term baby is born by normal delivery with maternal premature rupture of membranes for 29 hours. The mother deteriorated in the postpartum period with a sepsis-like-presentation and was admitted to the intensive care unit. The mother also had abnormal liver function tests and she was subsequently transferred to a specialist liver unit. The baby needed resuscitation with inflation and ventilation breaths for 2 minutes and was admitted to the special care baby unit (SCBU) on continuous positive airway pressure (CPAP).

An initial assessment was performed by an ANNP, who completed a NEWS scoring. This showed that the baby had a pulse of 153 beats/minute, a blood pressure of 54/36 mmHg, a respiratory rate of 64 breaths/minute and oxygen saturations of 91* on room air. The senior paediatrician was contacted for urgent assessment and advice.

What is the immediate priority intervention?

Stabilisation of the baby using the ABCDE approach. Increasing the concentration of oxygen was done by starting CPAP and oxygen in SCBU, and siting an intravenous (IV) cannula. First dose of IV antibiotics (benzylpenicillin and gentamicin) was administered at 45 minutes of age.

What are the urgent investigations?

Essential blood tests, such as full blood count, CRP, blood gas, blood glucose, blood culture, were carried out. In addition, a chest X-ray completed at 4 hours of age showed right-sided consolidation. The baby's initial CRP was 63 mg/L and the white cell count was 26.5x10 9 /L.

What other steps would need to be initiated?

Close monitoring of the baby with NEWS scoring was continued and a lumbar puncture considered. A cranial ultrasound scan may be considered, if there is evidence for meningitis because it will be useful to rule out major intracranial abnormalities or bleeds.

The blood culture results, available at 18 hours, showed Gram-negative rods that were later confirmed to be E. coli. The CPAP was weaned off on day 2 and the baby needed low flow oxygen for 2 further days. At 36 hours, CRP had increased to 107 mg/L and a lumbar puncture was done showing no pleocytosis. On advice from the microbiologist, the antibiotics were changed to IV cefotaxime for 14 days, with the mother also receiving 10 days of antibiotics as she gradually improved. A cranial ultrasound was performed on day 7 and was reported to be normal. The neonate was established on bottle-feeding and showed continued improvement. The baby was discharged on day 15 with the mother. At follow-up 2 months later, the baby was reported to be doing well.

Case 2. Late onset sepsis

A 2½ month-old female infant, born prematurely at 33 weeks' gestation and weighing 1.53 kg, was discharged home after an uneventful stay in the SCBU. The infant presented 2 days later with 24-hour history of poor feeding, drowsiness and low temperature.

The infant was assessed by the paediatric advanced nurse practitioner. On assessment the baby was drowsy, appeared mottled and was having intermittent short apnoeas. Observations showed a temperature of 35.2°C, heart rate of 170 beats/minute, respiratory rate of 62 cycles/minute, blood pressure of 48/28 mmHg, oxygen saturation 89* on room air, and central capillary refill time of 3-4 seconds. The infant was difficult to rouse and responding to voice on the AVPU scale, and appeared very pale. The rest of the clinical examination was normal.

Stabilisation using the ABCDE approach, ensure patency of airway, and intubate and ventilate, if necessary. Give an IV fluid bolus and start on IV cefotaxime, preferably after taking a blood culture.

What investigations might be helpful?

Blood investigations (full blood count, urea and electrolytes, CRP, coagulation screen, blood gas and glucose) and a blood culture. A CT scan should be considered and a lumbar puncture, when the infant is stable. Initial CRP was 32 mg/L and white cell count 17.3x10 9 /L. Blood gas showed a mixed acidosis with raised lactate of 6.5mmol/L. A CT scan done 1 hour later was normal. CRP peaked on day 3 at 69 mg/L and settled to normal levels by day 14.

The infant was intubated and ventilated and was transferred to the paediatric intensive care unit. At 48 hours, there was no growth from blood cultures. A lumbar puncture on day 3 showed a white cell count of 90x10 6 /L, glucose 1.2 mmol/L (concurrent blood glucose 4.6 mmol/L) and a Gram stain showed a Gram-positive coccus, confirmed to be GBS 24 hours later.

The diagnosis made was late onset GBS meningitis. The baby made a gradual recovery and was transferred back to the local unit on day 7. The baby received 21 days of IV antibiotics in total (changed from IV cefotaxime to IV benzylpenicillin on day 5). Although neonatal sepsis theoretically is considered to be in the first 28 days of life, GBS is known to cause LOS in babies up to 3 months of age, more so in premature babies. ( Stoll et al, 1996 ).

At discharge, the mother was informed that in future pregnancies the newborn baby would require GBS prophylactic treatment soon after birth. Clinical follow-up over the next 2 years found the infant to have normal neurodevelopment and she was discharged from paediatric care.

Neonatal sepsis can be difficult to diagnose due to its non-specific and varying presenting features. Early suspicion and appropriate management, along with administration of antibiotics within the golden hour is likely to be associated with a better outcome. It is important that health professionals remain aware of the risk factors and various red flag features in a neonate presenting with non-specific features.

• Neonatal sepsis can be associated with serious morbidity and mortality
• Two most common bacterial pathogens causing neonatal sepsis are Group B Streptococcus and Escherichia coli
• Early recognition and a structured approach are necessary for assessing neonates with suspected neonatal sepsis
• Input from senior clinicians should be sought early to expedite the decision-making process
• Administration of antibiotics within the golden ‘first’ hour is likely to be associated with a better outcome

CPD reflective questions

• Why is it important to identify neonatal sepsis early and refer for urgent assessment by the paediatric team?
• Nurses are suitably placed to identify and manage neonatal sepsis. Based on your experience, consider a few challenging scenarios you may have come across of neonatal sepsis and how these were managed
• Reflecting on the case studies in the article, can you identify three or four scenarios where nurses in different clinical settings have made a difference, either by recognising neonatal sepsis early or by identifying deterioration in clinical status through regular observations, or clinical assessment, and escalating concerns to senior health professionals?

Toggle Contents

• Aims and objectives
• Introducing case study
• Section 1: Sepsis information
• Section 2: Case study
• Supporting policies
• Identifying the priorities
• Reflections

Case Study: document.write(name);

Current situation.

• Heart rate: 115 beats per minute

Blood pressure

• SpO 2 : 94%
• Respiratory rate: 24 breaths per minute

History of the situation

General practitioner

Past medical history

She has arthritis in her knees which limits the distance she can walk and is on regular analgesia.

Ability to be independent

Treatment given in ed.

Emergency department

Urinalysis undertaken; nothing abnormal detected (NAD).

Sputum specimen sent to labs for analysis.

Effect of treatment in ED

Her systolic BP has increased and she is not as tachycardic now.

Temp 38.4°C - blood cultures have been taken. Tazocin is given. Nebulisers salbutamol and atrovent administered for a slight wheeze with good effect.

Blood Gas Result

Arterial Sample Time: 18:30

Handover from Emergency Department

Case Study: document.write(name); arrives

Medicine Chart for document.write(name);

Observation chart for document.write(name); (from 17:50), fluid chart for document.write(name); (from 18:00), fluid chart for document.write(name);, blood results for document.write(name); - serial results.

NB: Always check the normal values used by the laboratory you send blood samples to as these can vary between laboratories. These 'normal values' are given for the purpose of analysing blood results in this resource only. Always check local policy and local normal values before treating your patient.

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