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.

ADC/DFTB Journal Club #2 – December – How well do we manage suspected meningitis in ED?

Cite this article as:
Grace Leo. ADC/DFTB Journal Club #2 – December – How well do we manage suspected meningitis in ED?, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.17786

Vaccines have been instrumental in reducing rates of bacterial meningitis. However bacterial meningitis still represents 4-19% (1) of cases of meningitis and has been estimated to be cause 2% of all child deaths (2). Timely administration of antibiotics helps save lives with adult research suggesting that every hour of delayed treatment increases the risk of death or permanent disability by 10-30% (3). So how swiftly do we investigate and treat children with suspected meningitis? The paper from Archives of Disease of Childhood featured in our second #DFTB_JC sought to answer this question:

 

What’s it about?

This was a prospective cohort study of 388 children who attended three UK paediatric tertiary centres between 2011-2. They had been either hospitalised with suspected meningitis or underwent lumbar puncture (LP) during sepsis evaluation.

Of the 388 children, 18% (70) were given a diagnosis of meningitis but only 13 were documented as bacterial and 26 as viral with and 31 patients having no known or identified cause. Just over half the children (57%) had seen a doctor in the same illness prior to ED presentation.

The median time from initial hospital assessment to antibiotic administration was 3.1 hours.  The time to LP was even longer at 4.8 hours, but once discounting intentional postponement for reasons including convulsions, concern regarding raised intracranial pressure, coagulopathy or shock, this time reduced to 3 hours. Over half of the children (62%) had their LP following antibiotics.

In further discussion with the corresponding author @manishs_  the mean was chosen due to skewing of the data and the time from initial hospital assessment was equivalent to arrival in ED. The time between initial assessment and LP ranged from 0-183 hours whilst the time between initial assessment and antibiotics ranged from 0 to 136 hours. For the 221 patients who they had data in hours available; only 31 received antibiotics in the first hour. However 131 of the 221 patients did receive antibiotics in the first 4 hours.

 

 

The general sentiment from the twitter discussion was  that the median time of 3.1hours to antibiotic administration was longer than expected, and suboptimal. Whilst the actual time point may have been somewhat surprising; many could identify common reasons for antibiotic delay and in particular, discussion about the difficulties that lumbar puncture can pose in different age groups and its contribution towards delay of antibiotics.

“It surprised me. Think we generally give abx before LP in children and LP before abx in babies… probably because of less anxiety around the procedure in babies. But no excuse for 3 hour delay in any age group really.” – @DrRoseM

 

 

 

We then delved deeper into the importance of LP before or after antibiotics and factors affecting unintentional LP delay. Paediatrician from Ontario, Tom Lacroix shared concern that with improved vaccines, he has seen skill attrition.

“…I wonder how much of delay is bc we have become unaccustomed to doing LPs. I have seen a fall in LPs 90%+ since intro of pneumococcal conjugate vaccine” – @drtom_lacroix

Across in the UK, the perceived anxiety surrounding performing an LP in older children was raised including staffing challenges, concerns about pain and procedural sedation.

“In neonates we rush to get the LP done within an hour, but in older children it always seems to take a lot longer. Do we have misplaced anxiety in this age group?” – @TessaRDavis

“…It takes one NICU nurse to flex a 6 day old up for an LP, but a play specialist, at least two nurses and one parent to get an older child in position for an LP” – @edd_broad

Differences in practice in terms of performing a FBC and Coags screen prior to LP were also highlighted.

“Not sure about mandatory, but I’ve been taught (and continue to practice) confirming PLT > 50×10^9/L prior to LP. ” – @henrygoldstein

“…Unless evidence of coagulopathy ie purpura. Do LP and then give abx” – @DocAnthonyT

 

 

 

In the supplementary tables from the paper, of all children in the study, just under a quarter (24.7%) had bacterial and/or viral CSF PCR performed. Of the 70 children who had meningitis, CSF PCR was performed on only 9 (13%). The rate was slightly higher for meningitis of cause unknown (6 of 29 patients, 21%). The authors commented that this represents a significant underutilisation, particularly as CSF PCR is recommended in the current UK guidelines. The suspected cause of this was a long turnaround time to PCR.

However the benefits of positive viral CSF PCR results would include reducing length of treatment and inpatient stay as well as building a more accurate understanding of true disease rates.

The results of this paper contrast with experiences of our journal club participants where CSF PCR appeared to be a more common order, particularly in the neonatal setting:

“Might depend on the CSF WCC for the bacterial PCR? If zero, I wouldn’t necessarily send bacterial PCR (but will still frequently send viral PCR)…Parechovirus PCR is automatically sent for our neonates. #DFTB_JC ” – @DrSarahMcNab

“NICU where I work send viral PCRs as standard with turnaround in 24 hours. Think you still need to request in paeds. ” – @DavidKing83

 

Paediatric Registrar Rose provided a good summary of what she learned from the article and the #DFTB_JC chat:

take home- give the abx as soon as possible and definitely within 1 hour. If unable to do LP pre abx due to delays etc then do LP ASAP after abx. Consider PCR as a valuable tool to aid decision re duration of treatment” – @DrRoseM

From the DFTB team, the discussion has made us rethink how each step in assessment and management of suspected meningitis may delay optimal care. In particular we’ll be thinking about how strong the evidence is behind ‘the golden hour’ of antibiotic administration, the anxiety surrounding LPs in older children and evidence behind performing coagulation studies prior to LP…now that sounds like a potential post for the future.

Thanks again to everyone who participated in our #DFTB_JC and we hope you will join us again later this month for our next paper.

 

Please join us for our next ADC/DFTB Journal Club on twitter at Tue 22/1/19 at UTC2000hrs (That’s Wednesday 0700 23/1 AEST) January’s featured FREE access article from @ADC_BMJ featuring a FREE access article from the latest issues of Archives of Disease of Childhood. January’s pick  is ‘ Can we use POCUS to Diagnose Pneumonia?’ Read the article here: bit.ly/2TMDf2M The chat will happen on twitter, hosted by @DFTB_Bubbles. Remember to use the hashtag #DFTB_JC for all related posts.

Lumbar Puncture Needle Depth

Cite this article as:
Henry Goldstein. Lumbar Puncture Needle Depth, Don't Forget the Bubbles, 2018. Available at:
https://doi.org/10.31440/DFTB.14720

Recently, I prepared up to perform a lumbar puncture for the first time in a few months and a quiet voice at the back of my brain whispered ;

How deep would I need to go?
Which length needle would be the best?

I asked a handful of senior and junior colleagues, both at the time and in the writing of this post, and the response was almost universally “deep enough that the CSF comes out.” Certainly true, but not very pragmatic, and lacking the kind of detail I was hoping for…

Background:
I know there’s much discussion about the tip shape of a lumbar puncture needle, and in honesty, I’ve yet not read sufficiently to have strong opinions. However, in the fifteen minutes before the procedure, I had a look at the literature around needle length, and swiftly realized there was much more to this than I’d thought. Procedure finished, I was back to the drawing board.

Essentially, the balance is that a needle that is too short won’t reach the sub-arachnoid space, and a needle too long confers additional technical difficulty and increases the risk of going through.

So first, some basic anatomy; the aim of the exercise for lumbar puncture and CSF examination is to be in the sub-arachnoid space. To reach this space, the needle must pass through (in order) skin, superficial fascia, supraspinous ligament, interspinous ligament, ligamentum flavum, epidural space, dura mater and the arachnoid. I’m no neurosurgeon, but I’m pretty sure that it’s impossible to feel each of these layers on the end of the needle.

The anatomical target is either the L3/4 or L4/5 vertebral interspace, which respectively lie one vertebral body above & below the level of Tuffier’s line. Tuffier’s line is the imaginary line running between the superior iliac crests, and is used to demarcate the lower end of the spinal cord (which, in neonates, ends around L3 and moves superiorly with linear growth).

Finding a formula:
One of the more widely used formulas is from a 1997 paper where Craig et al. derived an elegant formula that;

 LP needle depth (cm) = 0.03 x height of child (cm).

Easily memorable and from a sample of 107 children receiving an LP with macroscopically clear CSF, the authors’ intention was a formula requiring only one variable that could be obtained in a critically unwell child – height being easily obtained with a measuring tape or Broselow tape.



In my department, the most common single measure recorded is weight; Bilic’s 2003 study of 195 Croatian children (over 3m of age) found the best correlate for LP depth was weight, using the formula

LP depth (cm) = 1.3 + (0.07 x Body weight (kg) )

The above formulae use a single variable and hence are probably more useful and pragmatic in the setting of an unwell child. Several other articles have discussed the most accurate formula for LP depth; all of which are reliant on at least two measured parameters. The following formulae may be more beneficial for elective CSF examination.



Several formulae were derived for LP depth from a cohort of 279 paediatric oncology patients in Malaysia; the best fit for their dataset was

y = 10 (weight (kg)/height (cm)) + 1

For this cohort, the LP depth was measured by perhaps a less reliable method than other datasets described, as the investigators measured the distance from their finger on the needle when pressed to the back at withdrawal. Irrespective, this paper summarizes many of the preceding papers in the discussion section.



Abe and foundation DFTB contributor Loren Yamamoto took a slightly different approach in a 2005 study; they reviewed 175 abdominal CTs to identify spinal canal depth at the iliac crest, deriving the formula of

LP depth (cm) = 1+ 17( weight/height).

Crucially, they went on to compare standard needle sizes to these depths to identify if the needle was too short or too long.

 

Defining the needle depth in this way has several benefits – firstly, it’s relatively prescriptive and secondly, it draws to attention the risks associated with using a needle that is too short (multiple punctures, anatomically impossible to reach the CSF), which amount to avoidable harm. In this context, it’s pertinent to know your tools. That is, identify which spinal needles are available in your department, their lengths and the type of tip.

LP needles are available in the following lengths (mm), depending on the brand, introducer, tip type: 25, 35, 38, 50, 64, 70, 75, 90, 103, 120, 150. Find the stock in your department  and see what’s there.

 

 

What about ultrasound?
The use of ultrasound to identify the depth of the spinal cord has been trialed in a number of papers; the two mentioned here were both produced from Addenbrooke’s Hospital in Cambridge, UK.

Firstly, in a neonatal population (105 neonates), weighing between 500g and 4500g, USS was used to measure median spinal cord depth (MSCD). They subsequently derived a formula of

LP depth (median spinal cord depth in mm) =  2(Weight) + 7 mm (R^2 0.76).

 

Subsequently, this nomogram was validated (albeit by the same author group and unit) in this study.

A later study by the same group undertook USS on 225 children aged 3m to 17 years presenting for echocardiography. The majority of patients were over 5 years of age. MSCD was identified as above, and a number of prediction models developed. The formula put forward by the group as satisfying the inherent tradeoff between accuracy (R^2 =0.72) and utility is

MSCD (mm)=0.4 W (kg)+20

 

So, does this change my practice? I will admit that I don’t have any of the above formulas fixed in my head, as yet.  Spinal needles in my hospital don’t have depth markings (it would be interesting to know if these exist). Instead, the above information serves to help in selecting a needle, particularly in those patients somewhere between neonate and adult sized. On this basis, I suspect I’m most likely to utilize formulae with weight as the single variable. I also went and re-read Ben Lawton’s post on champagne taps before the next one.

 

In summary;

  • Formulae are not yet in regular practice to identify needle depth for lumbar puncture.
  • We advocate increased awareness of the depth of the target structure, particularly when it comes to needle selection.
  • A needle can be too short, but it can’t be too long – it just becomes harder to use.

 

The 9th Bubble Wrap

Cite this article as:
Grace Leo. The 9th Bubble Wrap, Don't Forget the Bubbles, 2017. Available at:
https://doi.org/10.31440/DFTB.12336

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.

Pro tips for LPs in kids

Cite this article as:
Ben Lawton. Pro tips for LPs in kids, Don't Forget the Bubbles, 2015. Available at:
https://doi.org/10.31440/DFTB.7969

Though less commonly performed than it used to be, the lumbar puncture remains a key skill to master for anyone practising acute paediatrics. December’s Archives of Disease in Childhood Education and Practice contains an excellent paper entitled “How to use… lumbar puncture in children” (1), which flashes more pearls than a 4th of July garden party in the Hamptons. We share some of its wisdom below but highly recommend reading the paper to anyone who considers LP within their scope of practice.

How much is too much?

Adults have a CSF volume of about 150 mls and produce it at somewhere between 14-36 mls/hour. Neonates have about 50 mls of CSF, which they produce at a rate of 25 mls/day. Twenty drops of CSF equates to about 1 ml. How much CSF you need to take depends on what you want to do with it but 1.5 mls (or 30 drops) should be both safe and sufficient for your smallest patients.

It’s all about position

LP is commonly performed in the left lateral position in children. Hip flexion opens up the intervertebral spaces and makes the procedure easier. Neck flexion does nothing to help the procedure and will probably make it more uncomfortable for the child as well as making it harder for them to breathe. Supporting neonates in the sitting position with their hips flexed and their legs forward is associated with wider intervertebral spaces and less hypoxia than the left lateral position in this age group. Anecdotally I have recently changed my routine practice for neonatal LPs from left lateral to sitting and it also seems to be easier for holders with a wider range of experience to achieve an optimal position in relative comfort.

What am I aiming at?

The spinal cord in adults and older children ends around L1-L2, in neonates it extends down to L3. The sub-arachnoid space extends down to S2. L4-L5 is generally the best area to aim for (bearing in mind we are not always in the space we think we are) though L3-L4 is also OK. With the child in an appropriate position a line drawn between the most superior aspect of both Iliac crests (Tuffier’s line) crosses the midline over the body of L4 so the space just below this is ideal.

How deep do I need to go?

Medical folklore contains a few different answers to this question but the most scientific answer I have seen is following formula (2)

Depth (mm) = 0.4 x Weight (kg) + 20

So in a 10 kg child CSF should be found at a depth of 24 mm.

How can I make it more comfortable for the patient?

Use topical anaesthetic. EMLA has been shown to help in neonates(3). Post LP headache may be reduced by:

  • Using a smaller needle (25g in neonates, 22g in others)
  • Replacing stylet prior to needle withdrawal
  • Orientate the needle with the bevel parallel to the spine so it will separate the longitudinally running fibres of the Dura. (I think this feels natural in the left lateral position but requires more thought in the sitting position).

Have you thought about…

…CSF lactate? This is quite a good discriminator between viral and bacterial meningitis with levels over 3.5 suggestive of bacterial CNS infection. It’s not quite as accurate after antibiotic administration but may still be clinically useful.

…USS guidance? This is still waiting for a decisive trial in kids but small studies have shown it to be a promising option for further exploration.

Defence against the dark arts

Many a mythical formula has been conjured up to interpret a white cell count in the context of bloodstained CSF. The authors of this paper suggest you can get a feeling by comparing the ratio of white cells to red cells in the peripheral blood and basing your maths on this, but wisely acknowledge that accurate interpretation is difficult in this context. It’s also worth highlighting the well described trap that a normal CT does NOT exclude raised intracranial pressure.

Though LP is a procedure I perform fairly frequently this paper has shone a spotlight into several dusky areas of my knowledge and I hope it will suitably illuminate yours. Finally, if I am asked to supply a question for next year’s Christmas quiz it may well be “Where can you find Tuffier’s line?”.

References

  1. Schulga P, Grattan R, Napier C, et al. How to use… lumbar puncture in children. Arch Dis Child Educ Pract Ed 2015;100: 264–271.
  2. Bailie HC, Arthurs OJ, Murray MJ, et al. Weight-based determination of spinal canal depth for paediatric lumbar punctures. Arch Dis Child 2013;98:877–80.
  3. Kaur G, Gupta P, Kumar A. A randomized trial of eutectic mixture of local anesthetics during lumbar puncture in newborns. Arch Pediatr Adolesc Med 2003;157:1065–70.