Sepsis 2020

Cite this article as:
Emma Lim. Sepsis 2020, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32392

Where do we start?

Fever and suspected sepsis is our bread and butter. This post will take you through a whirlwind 2020 sepsis update. We’ll cover what sepsis is, how to recognize deterioration and the recent management updates in light of the new 2020 International Surviving Sepsis Campaign Guidelines1.

For me, it is all about “What keeps me up at night?” and there are two things I worry about. The first is missing cases of suspected sepsis.  Think back to all those hot, miserable children you sent home over your career and the heart sink you feel when someone says, “Remember that child you sent home yesterday?”.  My second worry is making bad choices; making mistakes about how much fluid to give or which antibiotics to choose or when to start inotropes.

What is sepsis?

Let’s start at the beginning. How do you get sepsis? A bacterial or viral infection causes a systemic, inflammatory response syndrome (SIRS). We are used to seeing children who have a fever and a fast heart rate or respiratory rate and a raised white cell count, for example with bronchiolitis. A certain proportion of those children will go on to get sepsis but not a lot.

Spotting sepsis in the paediatric ED is like a game of Where’s Wally: there are a whole lot of hot febrile children with accompanying hot cross parents. Fever is common but sepsis is rare – at a quick glance they all look like Wally, but, of course, there is actually only one real one and it takes a bit of time and patience to find him. It is the same with all those children with fever: around 55% have self-limiting viral infections, only 7-13% have serious bacterial infection (SBI)2-4 and only 1% have sepsis. The picture’s different in PICU; 10% of PICU admissions are for sepsis. The 2015 SPROUT study5 looked at 569 children in PICU with sepsis (8.2% point prevalence). 40% were caused by respiratory infections and 19% percent by bloodstream infections. A quarter (25%) of them died.

That quote “7-13% of febrile children have a serious bacterial infection” seems high. There are predefined criteria (such as pneumonia, urinary tract infection, meningitis, osteomyelitis, septic arthritis), but in a reductionist sense, sepsis is any infection that makes a child so unwell that they are admitted to hospital for more than 72 hours and need IV antibiotics. But, the need for admission is very subjective and dependent on the experience of the doctor and the parents’ level of concern.  The goal posts are constantly shifting.  Ten years ago, we would admit children with osteoarticular infections for 6 weeks of IV antibiotics. Now they can be in and out within 72 hours (with most of their course given orally). That doesn’t mean the infections have got less severe, it’s just that our treatments have changed.  And is a urinary tract infection over a year of age really a serious infection?  Most will get treated with a short course of oral antibiotics, as will children with pneumonia.  Because that’s a whole other controversy; reporting focal consolidation on a X ray is art not science and has been shown to be famously unreliable in double blind studies.  So if we remove children who have simple pneumonia, urinary tract infections in older children,  skin and soft tissue infections that do not have positive cultures, the number of true SBI is quite a lot less than the quoted 1 in 10.

Unbelievably, there is no good definition of ‘sepsis’ in paediatrics6, so we tend to use the adult Sepsis 3 definition7 which states:

“Sepsis is life threatening organ dysfunction caused by a dysregulated host immune response to infection including renal, respiratory, hepatic dysfunction or metabolic acidosis”. A small proportion of children or young people with sepsis will go into septic shock, where shock is defined as hypotension, or impaired perfusion requiring inotropes with a higher risk of death than sepsis.”

This doesn’t really help us spot sepsis early enough to prevent these children going into shock.  So far, there is no reliable way of pinpointing who these children are. However, there is some exciting news. 2020 has brought us new international evidence-based guidelines for the management of septic shock and sepsis associated organ dysfunction in children; the Surviving Sepsis Campaign.

This has been a huge piece of work by an incredible transatlantic consortium, including Mark Peters (for the horse’s mouth listen to our latest RCPCH Paediatric Sepsis Podcasts). I am going to take you through some of these recommendations, but I think everybody should read it themselves.  The consortium took 3 years and reviewed over 500 papers, but you only have to read this one paper, so go on, make your life easy!  

Spotting sepsis

Recommendation number one. In children who present acutely well, “we suggest implementing systematic screening for timely recognition.”

Take note of the word suggest. This means there is some, but not definitive, evidence. We all recognise systematic screening for sepsis is a huge problem for paediatricians. Most children with a fever have a self-limiting viral infection, and many of these children will have fever, tachycardia and tachypnoea. But most do not have sepsis.  However, if we use the UK-based NICE high-risk ‘Red Flag’ criteria, these children are all flagged as potentially having sepsis. They over-trigger, shown by a 2020 paper by Ruud Nijman which showed that 41% of all febrile children in PED present with warning signs of sepsis3. If you look at this paper in some detail, 50% of children aged 1-2 years triggered the NICE red high-risk category for tachycardia alone. This mirrors data from a local audit from the Great North Children’s Hospital Emergency Department, conducted between April and June of 2017. Of 868 patients, 5% had serious bacterial infections, but 50% triggered NICE high-risk criteria. Sam Romaine from Alderhey Children’s Hospital, and part of Enitan Carrol’s group, looked at 12,241 patients and again, 55% triggered NICE high risk criteria8. For a full critical review of Ruud’s paper, take a look at our Searching for Sepsis post.

The NICE high risk criteria have a very high sensitivity but limited specificity, which means although they ‘over-trigger’, if a child doesn’t have any red flags then they are potentially ‘good to go’, helping inform safe discharge.

Is there a better score?

For a long time, adults have used the Q-SOFA score, a quick sepsis related organ failure assessment. Typically, this adult score has performed poorly in children. Enitan Carroll’s group have looked at a modified Q-SOFA score called the LQ-SOFA score (L for Liverpool), modified to predict critical care admission rather than sepsis. Critical care admission is a more common outcome than sepsis, particularly relevant because this helps us understand which children are at risk of deterioration. The modified score, is made up of four simple, straightforward criteria, including capillary refill, AVPU (that’s Alert, Verbal, only to Pain or Unresponsive), heart rate and respiratory rate, purposefully not including blood pressure, making this quick and easy to use as a screening tool. But what did they find? Carroll’s group compared five different scores that could help us predict sepsis or deterioration: lactate, CRP, adult Q-SOFA, NICE and LQ-SOFA. Lactate performed the least well, CRP and Q-SOFA a little bit better, NICE high-risk criteria better again, but best of all was the LQ-SOFA score. 

This work suggests that there are more sensitive tools out there, but these need to be combined with some way of de-escalating children who trigger because most of these children have a SIRS response from a self-limiting viral infection and not sepsis. De-escalation is usually done by ‘a senior review,’ with the intention of differentiating the hot and bothered child who has a viral infection from early sepsis.

Listen to parents

There are many examples of systematic screening protocols, the best being electronic scores. But they are not perfect.  Most importantly, the good ones listen to parents. Parental concern or health professional concern is particularly important for children with complex medical conditions: neurodisability, recurrent chest infections, those with indwelling lines or fed by gastrostomy. These children often don’t have typical signs and symptoms that health care professionals associate with infections or sepsis, often presenting with nothing more than their parents saying that they’re not well or not quite themselves. These children can be hypothermic (due to hypothalamic dysfunction) and run ‘cold’ so when they get an infection, their temperature may goes up to ‘normal’ (37 degrees), not triggering at all. The presenting signs can be very, very subtle like not tolerating their feed, or vomiting, or they may just be miserable and unhappy. This is why any escalation tool or score must in some way include parental concern. The NICE sepsis guidelines from 2017 tells us to pay particular attention to ‘concerns expressed by parents, families or carers’, for example, changes from usual behaviour.’  We must not underestimate the expertise of parents and we should incorporate them into the team of people caring for their children.

Doctors can be wary of parental concern but if we look at a systematic review of family-initiated escalation of care for the deteriorating patients in hospital, we can see that this wariness is unfounded.  Gill et al 20169 looked at a systematic review of ten articles (all descriptive studies) over ten years evaluating response systems for patients and families; five described a triaged response; five reported systems for families to directly activate the rapid response team. There were a total of 426 family-initiated calls, range 0.17 to 11 per month, with no deaths reported. All calls were deemed to be appropriate and three calls resulted in intensive care unit admissions.”

I believe there is evidence that parents only escalate when they need to.  As one of our parents of a child with a complex medical condition said;

Please listen to us when we say something is not right, we can see subtle changes in children, in our children, in their health and behaviour. That may not be apparent to the casual observer or even health professionals like yourselves and children like them cannot speak for themselves. Therefore, as parents, we have to ensure that we advocate for them in the strongest possible terms. We do not think we are better than the team, nor are we full of our own importance. But we are simply trying to give a voice to our children as they don’t have one of their own.”

What do you do next?

The Surviving Sepsis campaign developed a management algorithm for children, and while it is useful, there’s a lot of information, for many different teams in a small space. Firstly, when you look closely, the lower half (in black) is actually all about management in a Paediatric Intensive Care (PICU) setting -treatment of refractory shock and advanced haemodynamic monitoring. For paediatric emergency physicians, there is a lot that has to happen first! Let’s break it down.

The first thing that the international guidelines asks us to do is get intravenous or intraosseous access. Please only have three tries at getting intravenous access and if this isn’t successful, go straight to intraosseous access. It’s a great safe route and can be much easier to get than intravenous especially in children with complex medical conditions whom may be difficult to cannulate. Although it may feel like using an IO in an awake child will be traumatic , flushing with 0.5mg/kg of 2% lignocaine before you infuse fluids, antibiotics and other drugs, will reduce the pain.

Test, tests, tests

Recommendation number two. Get a blood culture.

This should always be your next priority, as long as it does not delay treatment. Let’s just think for a moment about blood cultures. Blood cultures are old technology. They were developed in the 1950s and have not really changed since. Traditionally, blood cultures are read at 48 hours but often don’t give any definitive answer. The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS)10 was a prospective, multi-centre, cohort study of 2844 children under 18  with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 hospitals across Europe and incredibly in 50% of patients the causative organism remained unidentified! Alasdair Munroe explains more in his blood culture post.

What we really want is a point of care test, a test that takes less than 60 minutes, that can quickly differentiate between viral and bacterial infections at the child’s bedside11. Andreola et al12 (and more recent studies by Ruud Nijman again) looked at febrile children and infants in Emergency Departments and this is what they found:

White cell counts, we know, are not helpful. A raised white cell count has poor sensitivity and specificity, so while CRP is better and PCT better still there is room for improvement.  All these tests have problems with sensitivity which means there is still going to be a worrying number of falsely negative tests.  We know this, for example, in children with diseases that progress quickly like meningococcaemia or sepsis who can have normal inflammatory markers early on.

However, new tests are on the horizon. The PERFORM/IRIS group published a diagnostic test using a two-transcript host RNA signature that can discriminate between bacterial and viral infections in febrile children (Herberg, JAMA 2016), using gene arrays to demonstrate up or down regulation of protein expression. Sensitivity in the validation group was 100% and specificity 96.4%13.  

But we don’t just want to know if a child has a bacterial or viral infection, we really want a clinical predictor of severity that could tell us which children are going to get very ill.  We have a few tests, but they’re not very specific. We often look at blood gases, looking for a metabolic acidosis. But that is very broad. What about a lactate >2mmol/l? The international guidelines did not recommend the use of lactate as the evidence is lacking, although it can give an idea of the trend and whether a child is getting better or worse and is generally considered to be best practice and is already standard in adult sepsis. But this is in direct contrast to a study by Elliot Long and team published earlier this year14 looking at predictors of organ dysfunction in over 6000 children presenting to the ED with fever. A lactate of 4 or higher was one of the best performing ED predictor of new organ dysfunction, the need for inotropic support and the need for mechanical ventilation. Take a look at Deirdre Philbin’s DFTB review of the study.

More new tests are coming.  For example, interleukin 6 and 10 may be able to predict which children with febrile neutropenia have serious infections and mid regional pro-adrenoedullin (MR pro-ADM) may be a promising biomarker to predict sepsis and septic shock15. So, watch this space!

Antibiotics

Recommendation number three. Start broad-spectrum antibiotics.

Moving on from tests to treatment, we now want to look at recommendation number three, when to start broad-spectrum antibiotics. There is a change in timing here.

In children with septic shock, antimicrobial therapy should be started as soon as possible and within one hour of recognition of sepsis.”  But, in children with suspected sepsis (i.e. organ dysfunction, but not shock), most of the children we see, guidelines suggest starting antimicrobial treatment as soon as possible after evaluation – you have 3 hours not 1 hour16.

This is important, because it gives you a chance to do tests and decide whether the child in front of you has sepsis or just a SIRS response due to a viral infection. This has bigger implications than just saving hospital beds, because we know timely initial empirical antibiotics will save lives, but unnecessary antibiotic use for all children with fevers increases antibiotic side effects, antibiotic resistance and cost.

Antibiotic choice

There are other recommendations around antibiotics. Importantly, the new consensus recommends a broad-spectrum antibiotic therapy with one single drug in normal children, such as  cefotaxime or ceftriaxone or, if they are allergic, meropenem.

As a quick aside, let’s think about penicillin allergy.

It’s important to get a history and to understand what a ‘real’ penicillin allergy is. We see a lot of children who present with a vague story of having been given a couple of doses of penicillin many years ago, who developed a rash and have been labelled as ‘penicillin allergic’.  But doing that in the heat of the moment can be tricky.

Zagursky believes “Avoidance of cephalosporins, when they are the drug of choice in a penicillin-allergic individual, results in significant morbidity that outweighs the low risk of anaphylaxis. We conclude that there is ample evidence to allow the safe use of cephalosporins in patients with isolated confirmed penicillin or amoxicillin allergy”17

Studies have found the risk of crossover between penicillin/cephalosporin reactions is <1%, so using cephalosporins as a first line is safe.  If the child also has cephalosporin sensitivity, they may need a carbapenem like meropenem.  Later, please think about referring these children to your local allergy service for penicillin or cephalosporin de-labelling, which entails having an antibiotic challenge under controlled, safe circumstances.

Moving on… antibiotics in immunocompromised children

The guidelines suggest using empiric multi-drug therapy in children with immunocompromise and those at high risk for multi-drug resistant pathogens. In this case, you might choose piperacillin-tazobactam and, if shock is present, amikacin. You can add teicoplanin if you suspect a line infection, with rigors when flushing the line, or a line site infection, with redness around their exit site, or signs of any soft tissue cellulitis.

The recommendations also cover antimicrobial stewardship. Once the pathogen and sensitivities are available, the guidelines recommend narrowing antimicrobial therapy coverage. This means narrowing down the antibiotic to something specific to the clinical presentation, site of infection, or risk factors.  Ask yourself these questions:

  • Is the child is showing clinical improvement?
  • Can they have their antibiotics at home? (via a paediatric out-patient antibiotic service)
  • Can they switch to oral antibiotics?
  • Can they stop their antibiotics?  If you don’t find any bugs, and the child is well, then the guidelines recommend stopping antimicrobial therapy.

Remember to phone a friend

Infectious disease teams or microbiologists; you never need to make decisions alone. The guidelines recommended daily assessment with clinical laboratory assessment for de-escalation of antimicrobial therapy. Assessment includes a review of the ongoing indication for antibiotics after the first 48 hours and should be guided by results from microbiology, signs of clinical improvement and evidence of reducing inflammatory markers, such as a halving of CRP, or if the child’s fever has settled for more than 24 hours.

Fluids

Moving on from antibiotics to fluids. The Surviving Sepsis Campaign has another paediatric management algorithm for fluid and vasoactive drugs. It’s also quite busy, incorporating the results of the FEAST study18.  It’s split into two, a green side and a blue side. The green side is for children who live in healthcare systems without intensive care, while the blue side is healthcare systems with paediatric intensive care. The change boils down to being more cautious with fluids.  The guidelines recommend 10-20 ml/kg boluses. I suggest giving 10 ml/kg and then reassessing for signs of fluid overload with hepatomegaly and listening for basal crackles suggesting pulmonary oedema, repeating a second or third bolus as needed.  I use 10 ml/kg because it’s the same in sepsis, in neonates and in trauma.

If the child needs more volume, give them more volume; you can repeat 10ml/kg boluses up to 40 ml/kg or more as needed just use smaller aliquots.  Remember there may still be children who need big volumes of fluid early on, and we have PICU readily available and the technology to support children’s circulation and ventilation and ‘dry them out’ later.  There isn’t enough evidence to fluid restrict children with sepsis in the ‘resource rich’ world just yet but trials are ongoing. The Squeeze Canadian Critical Care Group19 has started a study, so watch this space for results.

Which fluids should you choose?

Please use crystalloids not colloids. And although historically we have used 0.9% saline, it is better to choose balanced or buffered solutions such as Ringer’s lactate or Plasmalyte. Too much saline can cause hyperchloremic acidosis.   

Inotropes

There has been a real sea change in our approach with inotropes. As we’re being more cautious with fluid resuscitation, we need to start giving inotropes earlier. After giving 40 to 60 ml/kg have your inotrope lined up ready to go.  There is good evidence that the drug of choice should be adrenaline20.  You can give adrenaline via a peripheral intravenous cannula or an intra osseous cannula safely if you don’t have central access. There have also been studies in adults that showed that peripheral adrenaline is also safe, especially when given for less than four hours or in a diluted dose.

Safety netting

Most of the febrile children we see will be discharged; safe discharge is a big priority because that’s what the majority of hot bothered children need: good advice and home care.  Winters (2017)21 looked at 33,000 children who were discharged from Emergency Departments with abnormal vital signs. 27,000 (80%) of them were discharged with normal vital signs, with only one case of potentially preventable permanent disability (a child who presented with tummy pains and came back with torsion of the testes, unlucky). 5,500 children (16%) were discharged with abnormal vital signs; there were no permanent disability or deaths from this group. So, you can send children home with fevers safely. But, the proviso to this is they need good safety netting on discharge, including both verbal and written information. This is one of the NICE recommendations. Our discharge safety netting leaflet22, which (gives some straightforward, practical information about giving anti-pyretic medication like paracetamol and ibuprofen), works like a ‘parent’s PEWS’ chart. It allows parents to see if their child is OK to stay at home or if they’re at some risk and should contact the GP, go to a walk in centre or call 111-advice line if they haven’t got better in 48 hours.  If the child is on the ‘high risk’ side, we want to see them back in the Paediatric Emergency Department.

In summary…

So, in summary, please screen for sepsis, we should all be doing it. I don’t know the best systems to help you but, ideally, you should have electronic observations, protocols and local guidelines.  Be aware that in the ED the incidence of sepsis is rare and that recent surviving sepsis campaign guidance suggests you can safely observe while you make a decision on treatment. Give antibiotics within 60 minutes in septic shock, but in sepsis with no shock you have three hours. If you are treating use fluid cautiously, with 10-20 ml/kg boluses and frequent reassessments.  Start adrenaline early if appropriate, and this can be given safely, peripherally.  Finally, safety netting is essential.

Thank you very much for reading this right through to the end! If you want to hear more, please have a listen to our Paediatric Sepsis podcast, hosted by the RCPCH.

Selected references

  1. Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. Weiss SL et al. Pediatr Crit Care Med. 2020 Feb;21(2):e52-e106. doi: 10.1097/PCC.0000000000002198.PMID: 32032273
  2. Craig JC et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594 10.1136/bmj.c1594
  3. Nijman RG et al. Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study. BMJ. 2013;346:f1706 10.1136/bmj.f1706
  4. van de Maat J et al. Antibiotic prescription for febrile children in European emergency departments: a cross-sectional, observational study. Lancet Infect Dis. 2019;19:382–91. 10.1016/S1473-3099(18)30672-8
  5. Weiss SL et al. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med. 2015 May 15;191(10):1147-57. doi: 10.1164/rccm.201412-2323OC. Erratum in: Am J Respir Crit Care Med. 2016 Jan 15;193(2):223-4. PMID: 25734408; PMCID: PMC4451622.
  6. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis.Pediatr Crit Care Med. 2005 Jan;6(1):2-8. doi: 10.1097/01.PCC.0000149131.72248.E6. PMID: 15636651 Review
  7. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Shankar-Hari M et al. Sepsis Definitions Task Force. JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289. PMID: 26903336
  8. Romaine ST et al. Accuracy of a Modified qSOFA Score for Predicting Critical Care Admission in Febrile Children. Pediatrics. 2020 Oct;146(4):e20200782. doi: 10.1542/peds.2020-0782. PMID: 32978294; PMCID: PMC7786830.
  9. Gill FJ et al. The Impact of Implementation of Family-Initiated Escalation of Care for the Deteriorating Patient in Hospital: A Systematic Review. Worldviews Evid Based Nurs. 2016 Aug;13(4):303-13. doi: 10.1111/wvn.12168. Epub 2016 Jun 3. PMID: 27258792.
  10. Martinón-Torres F et al. EUCLIDS Consortium. Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study. Lancet Child Adolesc Health. 2018 Jun;2(6):404-414. doi: 10.1016/S2352-4642(18)30113-5. Epub 2018 Apr 28. PMID: 30169282.
  11. Herberg JA et al. IRIS Consortium. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  12. Andreola, B et al. Procalcitonin and C-Reactive Protein as Diagnostic Markers of Severe Bacterial Infections in Febrile Infants and Children in the Emergency Department, The Pediatric Infectious Disease Journal: August 2007 – Volume 26 – Issue 8 – p 672-677. doi: 10.1097/INF.0b013e31806215e3
  13. Herberg JA et al. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children. JAMA. 2016 Aug 23-30;316(8):835-45. doi: 10.1001/jama.2016.11236. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 27552617; PMCID: PMC5997174.
  14. Long E, Solan T, Stephens DJ, et al. Febrile children in the Emergency Department: Frequency and predictors of poor outcome. Acta Paediatr. 2020; 00: 1– 10 
  15. Xia T, Xu X, Zhao N, Luo Z, Tang Y. Comparison of the diagnostic power of cytokine patterns and procalcitonin for predicting infection among paediatric haematology/oncology patients. Clin Microbiol Infect. 2016 Dec;22(12):996-1001. doi: 10.1016/j.cmi.2016.09.013. Epub 2016 Sep 22. PMID: 27665705.
  16. Elke G et al. SepNet Critical Care Trials Group. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis – a secondary analysis of a large randomised controlled trial. Crit Care. 2018 Mar 21;22(1):79. doi: 10.1186/s13054-018-2001-5. PMID: 29562917; PMCID: PMC5863464.
  17. Zagursky RJ, Pichichero ME. Cross-reactivity in β-Lactam Allergy. J Allergy Clin Immunol Pract. 2018 Jan-Feb;6(1):72-81.e1. doi: 10.1016/j.jaip.2017.08.027. Epub 2017 Oct 7. PMID: 29017833.
  18. Maitland K et al. FEAST Trial Group. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. doi: 10.1056/NEJMoa1101549. Epub 2011 May 26. PMID: 21615299.
  19. Parker, M.J., Thabane, L., Fox-Robichaud, A. et al. A trial to determine whether septic shock-reversal is quicker in pediatric patients randomized to an early goal-directed fluid-sparing strategy versus usual care (SQUEEZE): study protocol for a pilot randomized controlled trial. Trials 17, 556 (2016). https://doi.org/10.1186/s13063-016-1689-2
  20. Ramaswamy KN, Singhi S, Jayashree M, Bansal A, Nallasamy K. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med. 2016 Nov;17(11):e502-e512. doi: 10.1097/PCC.0000000000000954. PMID: 27673385.
  21. Winter J, Waxman MJ, Waterman G, Ata A, Frisch A, Collins KP, King C. Pediatric Patients Discharged from the Emergency Department with Abnormal Vital Signs. West J Emerg Med. 2017 Aug;18(5):878-883. doi: 10.5811/westjem.2017.5.33000. Epub 2017 Jul 19. PMID: 28874940; PMCID: PMC5576624.
  22. Lim E, Mistry RD, Battersby A, Dockerty K, Koshy A, Chopra MN, Carey MC, Latour JM. “How to Recognize if Your Child Is Seriously Ill” During COVID-19 Lockdown: An Evaluation of Parents’ Confidence and Health-Seeking Behaviors. Front Pediatr. 2020 Nov 17;8:580323. doi: 10.3389/fped.2020.580323. PMID: 33313025; PMCID: PMC7707121.

The 49th Bubble Wrap

Cite this article as:
Currie, V. The 49th Bubble Wrap, Don't Forget the Bubbles, 2021. Available at:
https://dontforgetthebubbles.com/the-49th-bubble-wrap/

With millions upon millions of journal articles being published every year it is impossible to keep up.  Every month we ask some of our friends from PERUKI (Paediatric Emergency Research in UK and Ireland) to point out something that has caught their eye.

Article 1: The associations between initial serum pH value and outcomes of paediatric out-of-hospital cardiac arrest

Okada A, Okada Y, Kandori K, Nakajima S, Okada N, Matsuyama T, Kitamura T, Hiromichi N, Iiduka R. Associations between initial serum pH value and outcomes of pediatric out-of-hospital cardiac arrest. Am J Emerg Med. 2021 Feb;40:89-95. doi: 10.1016/j.ajem.2020.12.032. Epub 2020 Dec 17. PMID: 33360395.

What’s it about? 

This paper reviewed the association between initial pH, obtained via intra-arrest VBG, and patient outcomes to evaluate if pH can be used to prognosticate in paediatric out of hospital cardiac arrest.

The authors reviewed a large, multicentre, prospective register of out-of-hospital cardiac arrests in 87 hospitals in Japan. They included paediatric out-of-hospital cardiac arrest patients younger than 16 between June 2014- December 2017 (458 patients included in the analysis – however over 35,000 listed in the registry). The primary outcome was 1-month survival. They divided the patients into four groups (based on initial pH on blood gas) and compared this to the patient’s ultimate outcome.

Interestingly, the median age of the patients was one year of age. Just over 6 in 10 of the patients were male. In 7 out of 10 patients, the first monitored rhythm was asystole. Cardiogenic arrest occurred in 4 out of 10 patients.

Mortality, and survival with good neurologic function, were lookd for. The overall survival rate at one month was just over 1 in 10 patients. In the group with pH > 6.82 survival rate was around 4 in 10 patients. However, with a pH< 6.47, thesurvival rate was 1 in 100 patients.

Of particular interest, in the entire study population of 458 patients, there were no patients who survived with good neurological function with a pH <6.8.

Why does it matter? 

Deciding when to stop resuscitation in a paediatric cardiac arrest can be difficult. Guidance is sparse and there are no universally recommended measures to help providers decide when to stop resuscitative measures. This is a stark contrast to adult cardiac arrest management where there are many validated termination of resuscitation rules based on measurements such as end-tidal CO2 s.

This is the first study to assess the association between pH and prognosis in paediatric out-of-hospital cardiac arrest. It presents robust evidence to support an objective, easily obtained measure that can be used to assist decision making around the termination of resuscitation. Important exclusions in this study were patients where resus was not attempted at a hospital, unknown age, traumatic or arrest secondary to hanging and those with no pre-hospital data.

This is an exciting paper providing guidance in an area sorely lacking any previous data. It gives providers a valuable tool that can substantially assist when making a difficult decision.

Clinically Relevant Bottom Line:

In out of hospital paediatric cardiac arrest, according to this study, no patients with a pH <6.8 survived with a neurologically favourable outcome. Survival in general was significantly lower in patients with an initial pH <6.8.

Reviewed by: Sean Croughan

Article 2: Should we be using focused cardiac ultrasound to guide therapy in children with sepsis?

Arnoldi s, Glau CL et al. integrating focused cardiac ultrasound into Pediatric septic shock assessment. Pediatr Crit Care Med. 2021 mar 1;22(3):262-274

What’s it about? 

This paper looks at whether the integration of FCU (focused cardiac ultrasound) in clinical assessment of children with sepsis would alter clinician’s evaluation of their haemodynamic characteristics.

The authors conducted a retrospective, observational study from January 2014 – December 2016 in a large PICU in America. They reviewed 74 PICU patients who received FCU within 72 hours of sepsis pathway initiation. Assessment by clinicians prior to FCU was compared to assessment after FCU in 46 patients, to determine if there was a difference in the haemodynamic characterisation of patients.

They demonstrated that incorporation of FCU changed the clinician characterisation of haemodynamic assessment made prior to FCU in more than 2 out of 3 of cases. The most common new finding identified post-FCU was myocardial dysfunction in (7 out of 22) cases. The most commonly ruled-out physiologies by clinician after FCU performance were obstructive physiology (5 in 8 cases), fluid responsiveness (13 in 26 cases).

Why does it matter? 

Sepsis in children continues to be one of the leading causes of mortality and morbidity worldwide.  Most children who die of sepsis suffer from refractory shock and/or multiple organ dysfunction within the initial 48 -72 hours of treatment, thus demonstrating the need for early and targeted interventions.

The previous method of classifying patients as having either ‘warm shock’ or ‘cold shock’ to guide therapy has been demonstrated to have poor correlation with cardiac function and systemic vascular resistance, and has not led to improved outcomes. It is now recommended that more advanced techniques such as focused cardiac ultrasound (FCU) be used alongside clinical assessment to identify haemodynamic status and direct therapy.  This is already widely the case in adult practice and algorithms have been created for its integration into patient management. 

Although this is a small study, it makes us think about the use of cardiac ultrasound alongside clinical assessment of children with sepsis in order to understand the haemodynamic characterisation of these patients.

This may be particularly useful in relation to fluid responsiveness, as half of the children who were thought to be fluid responsive pre-FCU, were found not to be after a FCU was performed. We know that children with sepsis often receive significantly more fluid per kilogram than adults which is associated with worse outcomes.

Clinically Relevant Bottom Line:

FCU, when incorporated into shock assessment, has the potential to identify myocardial dysfunction earlier and could result in reduced fluid administration as well as more targeted therapy based on haemodynamic status. However, further work is needed to determine how this can be used within paediatric practice.

Reviewed by: Laura Duthie

Article 3: Don’t forget the planet

Di Cicco, M.E., Ferrante, G., Amato, D., Capizzi, A., De Pieri, C., Ferraro, V.A., Furno, M., Tranchino, V., La Grutta, S. (2020) Climate Change and Childhood Respiratory Health: A Call to Action for Paediatricians. Int J Environ Res Public Health, Vol 24;17(15):5344

What’s it all about?

The authors conducted a systematic review looking at papers which examined the connection between respiratory illnesses in children aged 0 – 18 years. Keywords used separately and in combination were (allergic rhinitis, rhinitis, asthma, bronchitis, pneumonia, infections) and key environmental phrases (climate change, pollution, particulate matter, ozone, nitrogen dioxide, allergen, pollen). There was no limitation on the date of paper or country of origin.

Whilst much of the research at this stage is not completely conclusive key points from the review include:

  • Several studies from different countries found a connection between the increased prevalence of rhinitis and asthma, as well as the frequency of symptoms with increased global temperatures, which has changed many plant species’ lifecycles and led to longer pollen seasons
  • Positive correlations between the incidence of pneumonia and other acute respiratory tract infections in the context of increased extreme weather events such as heatwaves, fires and floods
  • Positive associations between the increased relative humidity and increased activity of respiratory viruses such as respiratory syncytial virus

Why does it matter?

Climate change is the long-term shift in weather conditions (temperature, humidity, winds and extreme weather events) and is often talked about in regards to protecting our wildlife or preventing further damage to our oceans and forests. It is less talked about when considering the impact on our own health. A child born in 2020 will live in a world that is more than 4 degrees warmer than the pre-industrial average, and subsequently will be at greater risk of a variety of acute illnesses as well as long term health consequences.

The Bottom Line:

More research needs to be done to accurately define the burden of climate change on our health. In the interim, we can all be environmental champions, from making changes in our own lives to reduce our carbon footprint as well as educating and influencing our colleagues and patients to do the same.

 …And for those with spare time; conducting research into the direct effects of climate change on specific health conditions along with contributing to government policies to create change at a higher level and reducing the carbon footprint of our healthcare systems are excellent places to start! 

Reviewed by: Tina Abi Abdallah

Article 4: Domo arigato, Mr Roboto

Littler BKM, Alessa T, Dimitri P, et al Reducing negative emotions in children using social robots: systematic reviewArchives of Disease in Childhood  Published Online First: 08 March 2021. doi: 10.1136/archdischild-2020-320721

What’s it about?

The paper looks at a number of studies that have used social robots in paediatric outpatient settings to interact and provide multi-sensory experiences to patients. The author postulates that using social robots provides better interaction and distraction for children, thus reducing anxiety and distress during the visit.

This systematic review managed to find ten studies that used social robots ranging from humanoid-based robots to ones simulating toy bears, dinosaurs and seals. The robots interact verbally and physically, and can respond to patient cues and tactile stimulation. They were used before or during the intervention. The studies included randomised controlled trials, exploratory trials, pilot and an observational study, with patient numbers varying from 2 to 73 (320 in total).

Why does it matter?

For lots of children a visit to the hospital can be a stressful and anxiety inducing event. There has been research to suggest that social robots have a positive impact on supporting adults with dementia and in children with autism they have been a useful tool in conducting therapy. The outcomes of this study were measured by observation, and by recording levels of distress, anxiety, pain and emotion using a variety of behavioural questionnaires. Overall, the feedback from the studies showed positive engagement from patients with their robots, reducing negative emotions, distress and pain.

The bottom line

There is promising data to suggest that robots may improve the experience of children in the healthcare environment. However, the evidence is weak due to the nature of the studies, lack of uniformity in the measurements, and low patient numbers. More research is needed on this topic to be able to really change practice but this sci-fi intervention may well become a reality in the not so distant future.

Reviewed by: Laura Riddick

Article 5: Children visiting the Paediatric emergency department during Ramadan

Sawaya,R., Wakil, C., et al (2021) Pediatric emergency department utilisation during Ramadan: a retrospective cross- sectional study. Archives of Disease in Childhood 2021;106:272-275.

What’s it about?

 This study looks to investigate the impact of Ramadan on patient characteristics, diagnoses and metrics in the paediatric emergency department (PED). There is limited data on how Ramadan impacts paediatric ED’s.

Why does it matter?

The authors looked at patient and illness characteristics as well as PED metrics including peak patient load, presentation timings, length of stay, time taken to order tests, receive samples and reporting of results to see how these were affected during the months of Ramadan and those before and after. 

This is a retrospective cross-sectional study on paediatric patients from 0 – 18 years presenting to a PED tertiary centre in Lebanon. Data was collected from all PED visits with any complaint at any time during Ramadan and the months (30days) before and after in 2016 and 2017. A bivariate analysis was performed between the Ramadan and non-Ramadan groups. The main outcomes were illness severity, chief complaints, final diagnoses, PED metrics including peak patient load, presentation timings, length of stay, and PED efficiency metrics such as time to order tests, times to samples being received and reported. 5711 patients were included and 1672 of these presented during Ramadan. There was no significant difference between age, gender or illness severity between the Ramadan or non-Ramadan group. This study found a significant difference in the number of GI complaints during Ramadan (39%) compared with the non-Ramadan group (35%). 

Trauma related complaints increased during Ramadan (3 in 100) vs (2 in 100) in non-Ramadan periods. Especially during the non-fasted periods of Ramadan (4 in 100) vs (2 in 100) during the fasted period of Ramadan. The number of daily visits during Ramadan (28.3) was reduced compared with non-Ramadan attendances (31.5). The Ramadan group did not have to wait longer for tests to be ordered or to have samples collected. 

This study was a single centre- and the charts that were reviewed did not have information on the patients individual fasting status. This would be interesting to see if the patient’s individual status affected diagnosis. The team used months immediately before and after Ramadan to reduce the confounding effects of seasonal bias.

Clinically Relevant Bottom Line:

This study revealed that there were some changes in GI and trauma presentations during the Ramadan period. There was also a reduction in cases presenting in this centre- this could help to influence staffing during this time if the patient population reflected that of the population in this study.

Reviewed by: Vicki Currie

If we have missed out on something useful or you think other articles are absolutely worth sharing, please add them in the comments!

That’s it for this month. Many thanks to all of our reviewers who have taken the time to scour the literature so you don’t have to.

All articles reviewed and edited by Vicki Currie

Septic for sure…

Cite this article as:
Deirdre Philbin. Septic for sure…, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.31704

Febrile children can pose a real challenge to clinicians in the Emergency Department. Identifying and trying to predict those who are at high risk of serious or invasive bacterial infection is particularly important as there are huge implications for altering the course of their illness, as well as for resource allocation and research initiatives. 

There are many clinical scores in use but, so far, their predictive performance for poor outcomes in undifferentiated febrile children is unknown.

Long E, Solan T, Stephens DJ, et al. Febrile children in the Emergency Department: Frequency and predictors of poor outcome. Acta Paediatr. 2020; 00: 1– 10 

What was the aim of this study?

This retrospective, observational study set out to determine the frequency of poor outcomes in undifferentiated children presenting to the ED with fever as well as evaluate predictors of poor outcome. The authors defined  ’poor outcome’ as the development of new organ dysfunction and the requirement for organ support therapy. They included initial vital signs, initial blood tests, and clinical scores as predictor variables.

What was the study design?

This is a retrospective cohort study. It was conducted in the ED in a large tertiary referral centre (single centre study) and full ethical approval was obtained.

Who were the study participants?

All children with ‘fever’ in their triage description or an initial triage temperature of >38.0°C were included, with no exclusion criteria.

How was the study performed?

Data was extracted from electronic medical records. This included demographic data, vital signs, blood test results, diagnosis, disposition, organ support therapies, organ dysfunction scores for patients admitted to PICU and mortality.

To ensure accuracy, one hundred electronic medical records were randomly selected and manually checked. 

What were the study team looking for?

The primary outcome of this study was the frequency of new organ dysfunction and requirement for organ support therapy in the study population, two indicators of severe illness. 

The study team examined the following variables to see if any could predict children at risk of poor outcome:

  • vital signs: heart rate, respiratory rate, blood pressure, and GCS
  • blood tests: venous lactate, creatinine, white cell count, platelet count, and INR
  • clinical scores: SIRS, qSOFA, and qPELOD-2

What kind of statistics did they use?

The chart above can be really helpful when thinking about statistical analysis. The type of data collected determines the most appropriate means of analysis. This study included both continuous and categorical variables.

For continuous variables, descriptive statistics were used i.e.  data was reported using median and inter-quartile ranges. 

In this study, continuous variables refer to demographic data such as age, sex, weight, vital signs (temperature, heart rate, blood pressure, respiratory rate, Glasgow coma score) and blood results (including lactate, creatinine, INR, platelet count and white cell count). The use of median and inter-quartile ranges is most appropriate for this type of data. The median is the value that is in the “middle” of the distribution, with 50% of the scores having a value larger than the median, and 50% of the scores having a value smaller than the median. The interquartile range (IQR) is the range of values within which reside in the middle 50% of the data. 

Frequency with percentage was used for categorical variables

For this study, categorical variables refer to the clinical scores used i.e. SIRS, qSOFA and qPELOD scores. Describing the data in this way is appropriate as it means the frequency that the data occurred may be expressed as a percentage. 

The association between initial vital signs, blood tests, clinical scores and the development of new organ dysfunction and requirement for organ support therapy were reported as odds ratios (OR) with 95% confidence intervals (CI). 

Odds ratios are usually used to compare the relative odds of the occurrence of the outcome of interest (e.g. development of new organ dysfunction), given exposure to the variable of interest (e.g. initial vital signs). The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. The confidence interval (CI)  is used to estimate the precision of the odds ratio and may be thought of as a way to measure how well your sample represents  the population you are studying.  A large CI indicates a low level of precision of the OR, whereas a small CI indicates a higher precision of the OR. This study uses 95% confidence intervals which means that there is a 95% probability that the confidence interval will contain the true population mean and in practice, is often used. 

The discriminative ability of predictor variables was measured using the area under the receiver operating characteristics curve (AUROC), with sensitivity and specificity calculated for each variable. i.e. vital signs, blood tests and clinical scores. 

The Receiver Operating Characteristic (ROC) curve is commonly used in statistics and can be confusing. Put simply, the curve is used to plot sensitivity versus false positive rate for several values of a diagnostic test. It is a graphical measure which illustrates the trade-off between sensitivity and specificity in tests that produce results on a numerical scale, rather than as an absolute positive or negative result. In this study, the AUROC is used to determine the sensitivity and specificity of each of the variables used. 

What were the results? 

Over the 6-month study period, 6217 (13.8%) children presented to the ED with a febrile illness. This represented  just over one-eighth of the overall presentations to the ED. Approximately two-thirds of these children were discharged home (65.4%), a third were admitted to hospital (34.6%), with 0.5% (32 of the 6217 children in the study) admitted to PICU. Slightly more than half of the children, at 58.3%, were under the age of 3. 

New organ dysfunction was very rare, in (0.4% or 27 children). 10 required organ support therapy (inotropes for 0.2%, mechanical ventilation in 6, renal replacement therapy in 1, and extra-corporeal life support in 1). 

The best performing ED predictors of new organ dysfunction were: GCS <11, INR≥ 1.2, lactate ≥ 4.0mmol/L, and qPELOD-2 (SBP) score ≥ 1.

The best performing predictors of the requirement for inotropic support were: initial hypotension using qPELOD 2 (SBP), lactate ≥4mmol/L, INR ≥ 1.2, and qPELOD (SBP) score ≥  1

The best predictors of the requirement for mechanical ventilation were: GCS <11, lactate ≥4mmol/L, INR ≥ 1.2 and qSOFA=3.

The bottom line

The bottom line from this study was that all predictor variables had poor test characteristics for the development of new organ dysfunction and the requirement for organ support therapy.

This is a good study; the results are easy to follow and, importantly, they meet the study aims.  The sample size is large, giving this study good internal validity, i.e. the extent to which the observed results represent the truth. 

Overall, this study supports our clinical experience. Poor outcomes in febrile children are, thankfully, rare. Less than half a percent of children in this study developed new organ dysfunction. Even fewer required organ support therapy. The infrequency of these outcomes in the study population however means that the use of “predictor variables” is not particularly helpful. A few take-home messages:

Vital signs – Elevated heart rate and respiratory rate were common findings in undifferentiated febrile children. This did not confer an increased risk for the development of organ dysfunction or the requirement for organ support therapy.

Take abnormal GCS seriously though – in this study, very few children had a GCS <11, but when it was low, GCS score was a strong predictor of the requirement for mechanical ventilation.

Blood tests – Remember to check lactate! Elevated venous lactate significantly increased the odds for the development of new organ dysfunction and the requirement for organ support therapy (both mechanical ventilation and inotropic support), with increasing risk the higher the lactate climbed. Elevated initial creatinine and initial INR also signified increasing severity of illness. 

Clinical scores – in this study, clinical scores performed variably. They can be helpful but may be more useful in the PICU setting. 

The external validity of this study is also strong; the results seem to be generalisable to our own population. Given the lack of exclusion criteria, the results of this study may be applied to any setting where undifferentiated febrile children are cared for. 

Were there any limitations to this study?

This is a retrospective, observational, single centre study using data extracted from an electronic medical record. Retrospective studies may be subject to information bias (by missing information) or by selection bias (because individuals are selected after the outcome has occurred). This study limited selection bias however by including all patients with fever. 


In addition, a single centre study may be limited by the use of local policies and guidelines rather than disease severity, reducing external validity / generalisability of the findings. 

The outcomes measured in this study are rare, but the authors attempted to overcome this by using a large sample size of over 6000 children. However, because the outcomes were so uncommon, the predictor variables had wide confidence intervals. 

Will this study change my practice?

This study is unlikely to change our practice. However, it does provide food for thought. It is in keeping with our clinical experience that the development of new organ dysfunction and the requirement for organ support therapy is rare among febrile children presenting to the ED. 

This study emphasises that predicting poor outcome in this patient group is difficult. Vital signs, blood tests and clinical scores were poor predictors. This highlights the importance of remaining particularly vigilant with respect to undifferentiated febrile children. 

A final comment from the authors – Elliott Long and Franz Babl

Thank-you for the opportunity to comment on our article titled ‘Febrile children in the Emergency Department: frequency and predictors of poor outcome’. The associated review covered all of the major aspects of the study.

A few additional points that may have been buried in the data: 

  • Though the study was primarily focused on severe infection (sepsis), we included a broader cohort of undifferentiated children with febrile illness presenting to the ED. This was somewhat exploratory, as we suspected that many children would be treated for sepsis (i.e.- admitted to hospital for IV antibiotics and one or more fluid bolus), but would not receive the diagnosis of sepsis. Interestingly, this was borne out in the study findings. The majority of children treated for sepsis did not receive the diagnosis of sepsis. This included the ‘severe end of the spectrum’ of children admitted to ICU; the most common diagnosis in this group of children was ‘acute febrile illness’. We interpreted this finding as being due to the hesitancy of clinicians to label undifferentiated febrile children with the diagnosis of ‘sepsis’ early in their treatment. Prospectively, we all hope kids will ‘turn the corner’ and physiologically improve after basic resuscitative measures… until they don’t! Also, children with more specific diagnoses, such as appendicitis or pneumonia, were more likely to receive these as working (admission) diagnoses even when at the severe end of the spectrum and receiving treatment consistent with sepsis. 
  • The majority of febrile children admitted to ICU did not require (new) organ support. These children included those with meningitis <2months of age, children with croup requiring multiple doses of nebulised adrenaline, children with pneumonia with large pleural effusions, and children on ventricular assist devices. These ICU admissions were based on local policy and procedure, and may not be generalisable to other health services. Studies using ICU admission as an outcome measure should be interpreted with this in mind. 

From a ‘big picture’ perspective, this study highlights two major issues for clinicians and researchers when dealing with sepsis.

  • Clinicians caring for children with febrile illness at different stages of their hospitalisation have different frames on the same disease that we all call sepsis. From an ED and acute care perspective, children with fever are un-differentiated, the majority have a mild, self-limited illness, and can be safely discharged home. The challenge for front line clinicians is early recognition of severe disease- finding the needle in the haystack. From an ICU perspective, children with fever are differentiated, the majority have severe disease and require close monitoring and/or organ support. The challenge in ICU is risk stratification. Understanding these differences in perspective is crucial for communication between clinicians caring for children at different stages of their hospital journey, and for researchers designing studies involving children with sepsis. 
  • As a result of poor outcomes being so rare, interventional trials that aim to capture patients at the entry point of acute care – before they are differentiated – will need to be pragmatic, large, and use composite outcomes. An example of such a study is PROMPT Bolus, which compares 0.9% saline to balanced fluids for sepsis resuscitation and initial maintenance. The study will include pragmatic entry criteria: patients receiving treatment for sepsis (IV antibiotics and >1 fluid bolus). The study will enrol >8000 patients from 3 research networks (PECARN in the United States, PREDICT in Australia / New Zealand, and PERC in Canada), and will use the composite outcome of Major Adverse Kidney Events on day 30 (MAKE30) as the primary outcome. This is probably the model that will be required to answer fundamental questions regarding early sepsis therapies in future.

Searching for sepsis

Cite this article as:
Anna Peters. Searching for sepsis, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.31160

The child with “fever” is one of the most common paediatric presentations to the emergency department. Most of these children are managed conservatively with parental reassurance and discharged home with a safety net identifying red flags. However, failing to identify those with “sepsis” has devastating consequences. How often do we get it wrong or worry about getting it wrong? We’d all love an evidence-based clear cut path for flagging and managing febrile children at risk of sepsis. Currently the approach in the UK is predicated on the NICE SEPSIS (NG 51) screening system which has anecdotally performed poorly with concerns it is poorly specific (i.e lots of false positives). Nijman and colleagues aimed to objectively assess the impact of the NICE Sepsis screening approach in children.

Nijman RG, Jorgensen R, Levin M, Herberg J and Maconochie IK. Management of Children With Fever at Risk for Paediatric Sepsis: A Prospective Study in Paediatric Emergency Care. Frontiers in Pediatric Care 2020; 8:548154. doi: 10.3389/fped.2020.548154

The lead authors looked at the various warning signs of serious infections in febrile children presenting to PED. Their aim was to then determine these children’s risk of having sepsis and to evaluate their subsequent management.

Who did they study?

Over 5000 children (5156 to be exact) aged 1 month to 16 years old presenting with fever over a period of 9 months from June 2014–March 2015 in a single PED at St Mary’s Hospital, UK were analysed.  Febrile children with no warning signs of sepsis were then excluded from the final cohort. The second largest group excluded from the final cohort was children with a complex medical history (n=119).  The decision to exclude this particular cohort is important given that ‘complex medical patients’ are more likely to have sepsis. The authors make the valid point that this group has features very different from the intended cohort, such as having different management plans in the context of fever. After these exclusions, plus a few further exclusions (lack of consent, lack of complete data or excluded because the child didn’t have any warning signs) the final cohort was of 1551 children. 

What did they do?

They first looked at the numbers of febrile children with tachycardia and tachypnea by using APLS and NICE (the National Institute of Healthcare Excellence) thresholds.  Subsequently, they looked at the numbers of febrile children fulfilling sepsis criteria by using well-known sepsis screening tools (NICE traffic light guidelines, SIRS, qSOFA, Sepsis Trust UK trigger criteria).

All the data for this study (vital signs, clinical signs and symptoms, tests, working diagnosis, need for hospital admission, timeliness of interventions) were collected electronically, having been recorded prospectively for all febrile children.

What did they look for? 

As a primary outcome the study determined:

  1. The incidence of febrile children who present with warning signs of sepsis 
  2. How often these children fulfilled paediatric sepsis criteria 
  3. How frequent invasive bacterial infections (IBIs) occurred in this population 
  4. How frequent PICU admissions occurred in this population.

Secondary outcomes included the compliance of clinicians with the paediatric sepsis 6 care bundle (PS6), what clinical interventions were and were not used from this care bundle and the timeliness of the interventions that were undertaken

What did they find? 

Almost a third of children aged 1 month to 16 years who presented to the PED had fever (28% to be exact).

41% of these febrile children had one or more warning signs (our study population).

The incidence of IBI was 0.39%. Of these children, only 0.3% required PICU admission.

This meant that using the sepsis guideline recommendations, 256 children would need to be treated to catch one IBI. Another way of saying this is the number needed to treat was 256. NNT for any serious outcome was 141.

How did the sepsis guidelines fare?

The thresholds for tachycardia and tachypnoea yielded a high false positive rate.

Adding sepsis criteria to predict the presence of a serious bacterial infection (SBI), IBI or PICU admission was also unreliable, with a lot of false positives.

Lactate levels were not significantly associated with the decision to give IV fluid bolus or presence of SBI, IBI or PICU admission. There WAS, however, a significant association between lactate levels and hospital admission.

Looking at the Paediatric Sepsis 6 Interventions, although many children triggered, two-thirds (65%) of the children with PS6 warning signs had none of PS6 interventions. And when it came to the ‘golden hour? Only a third (36%) of children with IBI or PICU admission received all PS6 interventions in the ‘golden hour with only 39 children (2%) receiving a fluid bolus

What does this all mean?

It is important to note that this study was only conducted in one single PED and in a time period that was before the NICE sepsis guidelines were formally implemented into practice.  The data was collected for this study via an electronic interface. While large amounts of data can be collected rapidly there can sometimes be gaps, either due to extraction issues or brevity on the behalf of clinicians that don’t give a comprehensive picture. Data were also only taken from initial triage and not from any clinical deterioration in the ED.  Given that acuity changes over time, especially in children with fever, this may have missed subsequent clinical change although is a pragmatic approach given the way that sepsis screening tools are applied in nearly all Emergency Departments. 

Numbers needed to treat were exceptionally high. Despite the allure of a protocol-based screening and management pathway,  the benefits of catching true sepsis early must be weighed against the possible unwanted effects of overtreating or overdiagnosing mostly well children in a potentially resource-stretched PED. The study really does highlight the difficulties we face when screening for a septic child in a generally well cohort, the ‘needle in a haystack’.

Essentially, what this study shows us is that serious infections are rare and most children who are categorised as ‘at risk of sepsis’ can in fact be managed conservatively with little intervention other than observation. It is clear that our current guidelines have very poor specificity; and while they tell us to investigate and treat lots of children, a lot of the time we as clinicians choose to rely on our clinical judgement and essentially ‘do nothing’. Observation and good clear red flagging must not be underestimated.  Instead of continuing to research more and better early predictors of sepsis, such as point of care biomarkers, perhaps we should be looking at this from another angle. The focus of the lens can also be flipped; we also need more research on how it can be safe NOT to do anything too. 

We’ll end with some thoughts from the authors

The Infections in Children in the Emergency Department (ICED) study is a single centre, prospective observational study. The study describes unique and carefully curated clinical data of febrile children with warning signs of sepsis, from a period prior to the implementation of the NICE sepsis guidelines. 

Our results confirm what many paediatricians dealing with acutely unwell febrile children already suspected: that many febrile children have warning signs of sepsis, but that the large majority have non-life threatening infections. 

Our findings will hopefully contribute to ongoing discussions about the use of sepsis screening tools in paediatric emergency medicine. Our study makes it clear that current tools lead to a high number of false positive cases, and their usefulness in routine clinical care in paediatric emergency medicine should be questioned. Escalation to senior decision makers of all children with warning signs of sepsis should be aspired, but is seldomly feasible in clinical practice and with unproven impact on reducing missed cases and optimising clinical care for the total cohort of febrile children. 

Although all children with serious infections would have been detected by the various sepsis tools, it is now evident that we need better tools to more selectively identify children at the highest risk of sepsis. Future studies should explore the utility of machine learning as well as the potential of combining clinical signs and symptoms with point of care biomarkers.

Ruud Nijman

The febrile infant conundrum

Cite this article as:
Dani Hall. The febrile infant conundrum, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.28850

It’s fair to say that febrile infants can be challenging. Often presenting with insidious symptoms but looking reasonably okay, they may still have life-changing or life-limiting illnesses like sepsis or meningitis. You could argue that we should take the view of eliminating risk, performing septic screens on all febrile babies, and admitting for IV antibiotics until their cultures are returned. The vast majority will have a benign viral illness but at least you can rest assured you didn’t miss a seriously sick infant.

And that’s what we did when I started my paediatric training back when the dinosaurs roamed the earth – every baby under 6 months (yes, you heard it right, 6 months) with a fever got a full septic screen, including lumbar puncture, and was admitted to the ward for at least 48 hours pending cultures. But, from a health economics point of view, this is, let’s just say, perhaps not the best way to allocate healthcare resources.

Over the years, researchers have tried to rationalise our approach to febrile infants. 2013 saw the first NICE fever in under 5s guideline; a year later a group from Spain published the Step by Step approach to identifying young febrile infants at low risk for invasive bacterial infection; and last year, the PECARN group published a clinical prediction rule for febrile infants under 60 days, which had excellent sensitivity and negative predictive values to rule out serious bacterial infections.

Last month, the Spanish group published an article looking at the external validity of the PECARN rule in their dataset.

Velasco R, Gomez B, Benito J, et al. Accuracy of PECARN rule for predicting serious bacterial infection in infants with fever without a source. Archives of Disease in Childhood Published Online First: 19 August 2020

PICO image

Before we plunge into the paper, let’s stop and think about a couple of important definitions here:

Serious bacterial infection (SBI) is used to describe bacteraemia, meningitis and urinary tract infections, also including infections such as pneumonia, skin, bone and joint infections, bacterial gastroenteritis and sometimes ENT infections.

Invasive bacterial infection (IBI) are infections where bacteria are isolated from a normally sterile body fluid, such as blood, CSF, joint, bone etc. An IBI is a type of SBI in a sterile site.

Who did they study?

Velasco’s group looked back at their registry of infants with a fever without source from a busy paediatric ED (> 50,000 presentations a year) in a tertiary hospital. To match the cohort in the PECARN paper, they used the following inclusion and exclusion criteria:

Inclusion: infants younger than 60 days who presented with a recorded fever, or history of recorded fever, of >38 C over an 11 year period between 2007 (when they started measuring procalcitonin) and 2018.

Exclusion: any infants whose history and/or examination pointed towards a focus, whose results didn’t include those used in the PECARN rule (absolute neutrophil count, PCT, urine dip), who didn’t have culture results, who were critically ill on presentation or who had a past history of prematurity, unexplained jaundice, previous antibiotics or other significant past medical history.

What were they looking for?

The group were interested to see how the PECARN rule fared in their dataset by looking at how many infants were predicted to be low-risk and yet had an SBI or IBI to assess the external validity of the rule.

What did they find?

1247 infants were included in this study. Of these, 256 (20.5%) were diagnosed with an SBI, including 38 (3.1%) with an IBI.

Of the 256 infants with an SBI, 26 (10%) were considered low risk by the rule. Of the 38 with an IBI, 5 were considered low risk (13.2%) by the rule. The PECARN rule would have missed 10% of infants with an SBI.

The PECARN rule’s sensitivity dropped from 97.7% in the original study to 89.8% and specificity dropped to from 60% in the original study to 55.5%.

So, how did Velasco’s group calculate the sensitivities and specificities of the PECARN rule for different groups in their dataset? They’ve nicely shown their data in 2 x 2 contingency tables in their figures. This is the data for SBI.

Table of data from Velasco study

So, we can see that sensitivity (those patients testing positive for the SBI as a proportion of all patients who definitely have SBI) = 230 / 256 = 89.8%. This means that 10.2% are falsely negative.

Specificity (those patients who test negative for SBI as a proportion of all of those who don’t have SBI) = 550 / 991 = 55.5%. This means that 44.5% are falsely positive.

What about infants with a really short duration of fever?

When the group looked at infants with a history of less than 6 hours of fever (n=684, a little over half of the cohort), the sensitivity dropped further to 88.6%.

Why did the PECARN rule perform less well in this study?

The authors offer up a number of suggestions, some of which are outlined below.

The populations may be slightly different. Although the authors attempted to exclude ‘critically ill’ infants from this study (as the PECARN study excluded ‘critically ill infants’), a precise definition wasn’t coded in the original Spanish registry. Instead, they excluded infants from this study if they were ‘not well looking’ or admitted to ICU. Because of the way the data was coded, some critically ill infants may have been included in this study’s dataset, skewing the results.

The Spanish database was of febrile infants without a source, excluding babies with respiratory symptoms, which may explain why the rates of SBI and IBI were much higher in this study than the PECARN database of febrile infants. So, although the PECARN rule was highly sensitive in their group of febrile infants, as in this study it may not perform so well in febrile infants without a source.

This study showed that the PECARN rule performed less well in infants with a short duration of fever. Overall, infants in the PECARN study had a longer history of fever at presentation – over a third of the PECARN infants had fever >12 hours compared to 11% in this study. Over half of the infants in this study presented within the first 6 hours. Blood tests are less sensitive in the first few hours of a febrile illness and this may well partially explain why the rule performed less well outside the PECARN dataset.

It’s important not to ignore this study’s limitations. The PECARN dataset recruited infants from multiple centres, while the registry for this study came from only one ED. As this study was a secondary analysis of a dataset, a power calculation wasn’t performed. Generally, a minimum of 100 cases is recommended for validating a model, but only 38 infants in this study had an IBI.

Study bottom line

This study showed that in the Spanish dataset of infants under 60 days with a fever without source, the PECARN rule performed less well than in the original study. This was especially true for infants with a short history of less than 6 hours of fever.

Clinical bottom line by Damian Roland

In Kuppermann et al’s original 2019 study febrile infants 60 days and younger were demonstrated to be at low risk of SBIs using 3 laboratory test results: Urinalysis, Absolute Neutrophil Count (ANC), and serum procalcitonin (PCT) levels. The study was well designed and therefore compelling in providing a framework in which to manage these challenging presentations. However, with respect to knowledge translation, external validity is critical. The availability of PCT is a significant limiting factor to being able to show the PECARN approach could be reproduced internationally. While PCT is used in Europe and Australia, it’s certainly not widespread in the UK where I practice, and then it is only used routinely in a very small number of hospitals. This makes Velasco and colleagues’ work really important as they were able to replicate the requirements of the original study and helps answer an important question: should centres start introducing PCT into their diagnostic pathology panels? The results of this study will be interpreted differently by different observers as ultimately the question is of risk tolerance. Personally, a 10% false-negative rate (if this is indeed the case) for an outcome that could result in long term disability feels uncomfortable. Counselling a parent that they could return home without treatment knowing this would probably be quite challenging. I am not sure many departments would be rushing to buy point of care PCT.

However, there are two very important caveats.  Firstly, is the validation cohort different from my own local cohort? The prevalence of disease has a huge bearing on the accuracy of any test. Knowing the local incidence of SBI and IBI in your own institution is important (but actually getting the numbers is harder than you may think!). It is likely that the PECARN approach may perform more effectively in other centres. Importantly the original paper highlights that implementation may be more effective in the second month of life due to the impact of HSV and other peri-natal infections present at 0-30 days. Secondly, what is the threshold for undertaking the blood tests in the first place? Fever in an infant less than 3 months is an interesting area as it’s one of the very few presentations in which a solitary symptom or sign is independently predictive of risk. Regardless of how the child appears to a health care professional, there is a risk of SBI and IBI (of anywhere between 2-10%) just by having a fever. This does mean that sometimes there is variation in approaches when there is a history of fever rather than a documented fever (for fear of not wanting to do a battery on tests on a neonate who in front of you appears completely well and has normal observations). But more importantly, this has led to an approach where although blood tests are taken, the results are often disregarded as an LP will be done and antibiotics will be given regardless. There are many cultural practices that have evolved around the management of the febrile neonate both within individuals and institutions. While in a study situation these are controlled for, their influence in the real world can not be underestimated and this is why it’s so important we have some pragmatic studies in this area.

This study makes me more determined to define our incidence of SBI locally and work out what impact new approaches to management may have. I think all centres should probably be doing this. However knowing the potential uncertainty in the sensitivity of the PECARN approach means it’s unlikely to be adopted in the immediate future without further validation.  

**post blog addendum 1st September 2020**

While this blog was in post production phase Kuppermann and colleagues have released further data on implementing their original predictive rule. This work has been summarised by Dr. Kuppermann below (click on to go to the original thread) and provides useful context to the discussion about external validity and implementation – DR.

Does Every Child With Fever Have Sepsis? Damian Roland at DFTB19

Cite this article as:
Team DFTB. Does Every Child With Fever Have Sepsis? Damian Roland at DFTB19, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.20382

Damian Roland is a Paediatric Emergency Medicine and Honorary Associate Professor, who is also the chair PERUKI (Paediatric Emergency Research United Kingdom and Ireland). Damian delivered this thought-provoking talk on guidelines, gestalt and real-world practice on behalf of Rachel Rowlands, who was unable to attend. You can follow him in Twitter at @Damian_Roland 

#doodlemed on this talk by @char_durand below

This talk was recorded live at DFTB19 in London, England. With the theme of  “The Journey” we wanted to consider the journeys our patients and their families go on, both metaphorical and literal. DFTB21 will be held in Brisbane, Australia.

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