Author Archives: PEMLit

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Reviewing the PEM Literature for your interest and development! #FOAMed @PEMLit

1st February 2013: Plain XR for Paediatric Patellar Subluxation

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Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23357381

What is this paper about (what is the research question)?

Do plain post-reduction XRs provide clinically useful and ED management-altering information in paediatric patients with patellar subluxation?

Summary of the Paper

Design: retrospective chart review

Objective:  to estimate the incidence of fractures detected on post-reduction XRs for patients with lateral patellar subluxation and to identify whether (and how) the presence or absence of a fracture alters ED management

Outcome: primary – presence or absence of fracture on post-reduction XRs for patients with lateral patellar subluxation. Secondary – differences in ED management between patients with and without fractures on plain post-reduction films.

Population:  patients <21 years presenting to the ED of a tertiary children’s hospital between January 1st 2000 and 31st December 2010

  • Inclusion: ICD coding related to patellar dislocation with reduction in the ED
  • Exclusion: patients with medial or intra-articular dislocations, patients with spontaneous reduction

Results: 80 patients identified of whom 79 (98.8%) underwent reduction of their dislocation/subluxation in the ED.

11 (13.7%) of patients had a pre-reduction XR – none of these had a fracture identified by radiologist report.

74 (92.5%) of patients had a post-reduction XR – fractures were idenfied in 8 cases (10%: 95% CI 3-17)

Patients with both pre- and post-reduction XR had a longer length of ED stay (median 3.4h, range 1.5-5.2h) compared with those receiving a single XR set only (median 1.9h, range 0.6-6.0h).

All patients, regardless of presence or absence of fracture, had uneventful reduction and were discharged with knee immobilisation and outpatient follow-up.

Authors’ Conclusions:

Pediatric patients with lateral patellar dislocations may be candidates for discharge from the ED after reduction without plain radiography. The modality by which to best determine the presence of a complicating osteochondral fracture (i.e., plain radiography, computed tomography, MRI, or arthroscopy) may be left to the discretion of the orthopedic surgeon accepting the child in follow-up.

On the study design

A nice short paper this week – and a relevant question – do we need to XR knees post-reduction of patellar subluxation/dislocation?

A couple of methodological issues with this one though. Retrospective studies are always open to bias – in this case, relying on ICD-9 classification introduces a potential for selection bias as we are reliant upon the accuracy of coded data to identify our patient cohort. However, with such small numbers (only 80 patients in an 11-year period) a prospective study is unlikely to generate enough subjects to maintain momentum and as such retrospective data collection is far more pragmatic.

The wide timeframe, while providing a reasonable sample size (albeit difficult to guage in terms of its epidemiological accuracy) does open the study up to the confounding effect of changes in practice. Arguably the introduction of alternative imaging modalities (ultrasound) and the relative availability of MRI scan might impact clinician decisions regarding whether to perform post-reduction XRs. The study can give us no account of this.

The other major issue is the lack of blinding in the data collection stage; this paragraph of the methods section is particularly interesting as it sounds as though the research assistant was specfically trained to identify qualities and points of interest among the identified case notes – this would almost certainly introduced an element of observation bias, exacerbated by the use of a single unblinded data collector.

Still, formal radiology reporting was used to determine the presence or absence of fractures – a reasonable standard. Given that the article talks about the use of other imaging modalities, it’s hard not to wonder how the radiology report might have been influenced; they were almost certainly not blinded to the clinical data, were CT/MR reports also available which might have “added” to the interpretation of plain films? When were reports made relative to the injury and availability of other imaging?

What were the results and what does this mean?

First, let’s look at pre-reduction films. These were taken in 11 patients. We know from the paper that in 79/80 patients the clinician had documented that there was clinically visible displacement of the patella laterally. So why the XRs? Habit perhaps? In fact, of those without pre-reduction XRs, 68/69 had specific documentation about the clinically visible displacement (so that’s where the 1/80 was) – simple maths tells us that all 11 patients having pre-reduction films had dislocation/subluxation apparent on examination alone.

And for the post-reduction films; these were performed in 74/80 patients (92.5%). 8 patients had fractures (10%), of whom none had pre-reduction films taken. None of the patients required intervention beyond ED reduction apart from a multiply injured patient whose patella was reduced in theatre while other injuries were being treated.

So, for all the methodological problems, it doesn’t look as though plain films – with or without fractures – change our ED management.

What can we take from this paper into clinical practice?

Well, from this small and moderately flawed study, it doesn’t look as though plain XRs add anything to ED management of patellar subluxation/dislocation. I certainly can’t think of a time in my clinical practice when a post-reduction film has led to admission (assuming reduction was successful, of course). So why do we do them?

What we don’t know is how these patients are subsequently managed at outpatient clinic. While CT/MR scans are more sensitive (see discussion section of paper for references) for identifying osteochondral fractures, does the presence of a fracture on plain film have important prognostic significance? Does it lead to earlier operative intervention or increased likelihood of operative management?

So not quite enough to throw plain films out altogether, but certainly worth exploring with a longer study period to include follow-up, together with some good quality orthopaedic opinion (other than, “get an x-ray because that’s what we do”).

More questions to ask

  •  Can this data be extrapolated to patients with spontaneous reduction and are these patients routinely x-rayed in any case?
  • Would a period of follow-up including outpatient review change the outcomes of this paper? Would we discover that the patients with fractures who were discharged should have had emergency treatment?
  • How does this sit with our orthopaedic colleagues?

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25th January 2013: Derivation of a Clinical Prediction Rule for Non-Accidental Head Injury

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Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23314183

What is this paper about (what is the research question)?

Can we identify children whose head injury is non-accidentally occurring using the presence or absence of certain clinical criteria?

Summary of the Paper

Design: multicentre prospective observational cross-sectional study

Objective: to identify and measure relationships between clinical variables and non-accidental head injury at time of PICU admission

Tests of Interest: a list of clinical and radiological findings

Reference Standard: a priori definition criteria for non-accidental head injury

Primary outcome: test characteristics with sensitivity, specificity and reliability, combined into a decision tree

Population: PICU patients across 14 participating sites, recruited between Feb 2010 and August 2011

  • Inclusion: children <3yrs of age admitted to PICU for treatment of symptomatic acute closed traumatic head injuries
  • Exclusion: pre-existing brain malformation identified on CT, absence of acute head trauma, head trauma from RTC.

Results: 209 patients recruited, of whom 45% (95) met one or more of the criteria for non-accidental head injury defined a priori. Of these patients, abuse was admitted by the perpetrator in 14 cases and moderately-strongly suspected (2+ extracranial injuries) in 53 cases.

20 variables were both reliable and descriminating of which 13 were based on information available at or near to the time of PICU admission. Binary recursive  partitioning identified five variables present at or near the time of PICU admission which, when used alone or in combination, identified 92 (97%) of those meeting the a priori defined criteria;

  1. acute respiratory compromise prior to admission
  2. seizures or acute encephalopathy
  3. bruising of the ear, neck or torso
  4. interhemispheric or bilateral subdural haemorrhage or fluid collection
  5. skull fracture other than isolated linear non-diastatic parietal fracture

For the five-part rule:

Sensitivity 0.97 (95% CI 0.90-0.99)

Specificity 0.27 (95% CI 0.20-0.37)

Positive predictive value 0.53 (95% CI 0.45-0.60)

Negative predictive value 0.91 (95% CI 0.75-0.98)

LR+ 1.33 (95% CI 1.18-1.50)

LR- 0.12 (95% CI 0.04-0.37)

Authors’ Conclusions:

Once validated, the rule could be used by paediatric intensivists to calculate an evidence-based, patient-specific estimate of abuse probability that can inform – not dictate – early decisions to launch or forego an evaluation for abuse.

On the study design

The methodology here is quite complicated. Essentially, the authors have decided in advance some criteria which cause or allow a high probability of non-accidental trauma as the cause of head injury in their PICU population (let’s call these reference critera). They have then measured the presence or absence of historical, examination or radiological findings and, while measuring the reliability of their assessment of the presence or absence of the findings, have correlated the presence or absence of the finding with non-accidental trauma as defined by the reference criteria. The individual findings were divided into “early” or “late” to help determine those likely to be present at the time of PICU admission, and the most reliable and discriminating criteria identified.

These were then combined into a decision rule which was applied to the population again, and test characteristics calculated. Phew!

There are a few problems here, most of which the authors identify. The major issue is true of all non-accidental injuries; there is no certainty in the diagnosis, no gold standard, and as anyone working in child protection knows identifying children who have been intentionally or neglectfully injured is a game of probability in the absence of confession (and even then not always a certainty). Vigilance is key; overdiagnosis causes a massive workload for paediatricians and enormous stress for families and patients (who are often separated during investigations), underdiagnosis fails the child and the family, often with tragic, deadly consequences.

The criteria used as a reference standard (table 2) are a reasonable surrogate for a gold standard.

230113 Table2

The other problem we have is that this is a very select population; by definition, these are the more severely injured children and it is likely that a significant proportion of non-accidentally head injured children will not require PICU. This immediately affects the extent to which we can generalise the findings to our significantly different PED population.

What were the results and what does this mean?

Figure 2 shows the decision tree the authors developed from the most reliable and discriminating variables.

250113 Fig2

The authors have then calculated the test characteristics for the decision tree as shown in table 6.

250113 Table6

As we can see by looking at the decision tree, the tool is far more sensitive than specific, thereby acting as a better tool to rule out NAI than ruling it in. In fact, the sensitivity is perhaps not as good as we would like (look at the 95% confidence interval – it could be as low as 90%). We can see that 3 patients classified a priori as high risk were misclassified by this tool as low risk.

The negative likelihood ratio is small, suggesting that a negative result in this population (with a low pre-test probability) produces a very low post-test probability, but again the confidence interval is quite wide.

The authors concede that adding any further variables would make the rule too complicated to be practical, which seems reasonable, but it does leave us wondering whether this rule will be fit for purpose with a potentially low NPV and sensitivity.

What can we take from this paper into clinical practice?

While this decision tree might, once validated, help to rule-out non-accidental head injury in the PICU population, the patients here are just too different from the PED population for this to be useful.

In addition, our job in PED is to resuscitate these children and while it is essential that NAI is always on the mind of the PED doctor, for these patients stabilisation and management of the acute injuries must take priority. Does this rule add anything to our PED assessment? I don’t think so – these are not the patients in whom I want to think carefully about NAI as my priorities are different; they have immediate clinical needs and NAI can be considered in more depth later. The patients in whom I want to rule NAI out are altogether less unwell. Any one of these five findings necessitates further PED assessment of the child from a perspective other than NAI.

It’s not a bad paper – it just doesn’t help us in PED.

More questions to ask

  • How does this rule perform in other PICUs (validation)?
  • How sure do we want to be of ruling out NAI (what sensitivity level should we accept in a tool like this)?
  • Does it have any predictive value for patients in the PED? Are there other cues which do have useful rule-in or rule-out potential in the less seriously injured head injury patients in PED?

Follow us on twitter: @PEMLit

4th January 2013: Comparison of Rectal, Axillary, Tympanic, and Temporal Artery Thermometry in the Pediatric ER

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Happy New Year from PEMLit!

Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23283266

What is this paper about (what is the research question)?

Which method of temperature measurement – axillary, tympanic or temporal artery thermometry – is the best predictor of rectal temperature in febrile and afebrile children?

Summary of the Paper

Design: Prospective single-centre observational (?diagnostic) study

Objective: to determine the most accurate non-invasive method of thermometry

Tests of Interest: Axillary digital thermometer – 5 minutes. Tympanic infrared thermometry as per manufacturer’s instructions (right and left ears). Temporal artery thermometry as per manufacturer’s instructions.

Reference Standard: rectal thermometry – mercury thermometer for 3 minutes.

Primary outcome: test characteristics and correlation coefficients for each method.

Population: Children aged 2-12 years presenting to the Emergency Room of a single centre in Delhi, India.

  • Inclusion: Not clear from methods section
  • Exclusion: Abnormal ear or rectal anatomy, thermoregulatory disturbances, family history of malignant hyperthermia, diaphoresis, Hb <8g/dL, severe malnutrition/severe wasting (WHO classification), uncooperative, crying, unconscious.

Results: 100 patients were enrolled, 50 “febrile” (Rectal T>38) and 50 “afebrile”.

Temporal artery thermometry had the highest correlation coefficient for both febrile (0.99) and afebrile (0.91) children.

In the detection of fever;

Axillary thermometry had sensitivity 80% and specificity 100% (no confidence intervals given).

Tympanic thermometry had sensitivity 98% and specificity 98% (no confidence intervals given).

Temporal artery thermometry had sensitivity 80% and specificity 98% (no confidence intervals given).

Authors’ Conclusions:

Temporal artery thermometry has the potential to replace rectal thermometry in the busy Emergency Room setting among children aged 2-12 years.

On the study design

Papers like this make me so sad! This could be such a great study – I’ve been asking the question “how should we measure temperature and what do we mean by fever?” for such a long time, and this simple study design has great potential to answer the question. Rectal thermometry is upheld as the “gold standard” in determining temperature but is not without risk.

Unfortunately, there are a few gaps. We don’t know how the patients were selected, so there could be all sort of bias and confounders we don’t know about. And what about excluding children who were crying? OK, it might make them a bit warmer – but who’s been in a Paediatric ED which isn’t filled with crying children?!

That said, they have a good size sample (100 subjects) and seem to have powered the study appropriately. But another question that arises is about the reliability of the measurements, in particular their standard rectal (mercury) thermometry. Who was reading these temperatures? How do we know their assessment is reliable – where is the kappa score?

What were the results and what does this mean?

040113Table2Table3

In terms of correlation with rectal temperature, termporal artery thermometry came closest, with temperatures in 50/50 febrile and 49/50 afebrile children reading within +/- 0.4 degrees of their rectal temperature.

Axillary temperature seemed to correlate better in both groups than tympanic temperature.

040113Table5

Tympanic thermometry had the highest sensitivity for detecting fever (98%), making it the best at ruling fever out, while axillary thermometry was the most specific (100%). No confidence intervals were given. Are these figures useful in clinical practice? No, probably not.

What can we take from this paper into clinical practice?

Despite the suspicious methodology, it certainly seems as though infrared temporal artery thermometry is the closest proxy for rectal thermometry, and with 99% of measurements within +/-0.4 degrees it seems reasonable to suggest it as the preferred method of ED thermometry in those aged 2-12 years.

More questions to ask

  • As a gold standard, how reliable is rectal thermometry?
  • What is the best method for children under 2 years of age, for whom tympanic thermometry is not considered to be an option?

Follow us on twitter: @PEMLit

14th December 2012: Ibuprofen & Codeine for Pain Management in Children

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Where can I find this paper?

http://www.jem-journal.com/article/S0736-4679(12)01136-5/abstract

What is this paper about (what is the research question)?

Is codeine in combination with ibuprofen better at improving paediatric pain scores for children presenting to the ED with limb injuries than ibuprofen alone?

Summary of the Paper

Design: single centre, randomised, double-blinded placebo-controlled trial

Objective: to compare the efficacy of a combination of codeine with ibuprofen to codeine alone for the management of pain in children with limb injuries presenting to the ED.

Computer generated block randomisation with double blinding was used.

Intervention: 1mg/kg codeine syrup plus 10mg/kg ibuprofen caplet

Comparison: placebo syrup plus 10mg/kg ibuprofen caplet

Primary outcome: difference in mean pain score between initial score at triage (T1) and 90mins after administration of medication (T3). Validated visual analogue scale (VAS) was used for pain scoring.

Population: children aged 7-18 years presenting to a tertiary paediatric ED between Feb 2008-Nov 2009, between 10am-4pm, with musculoskeletal limb injury in preceding 72h

  • Inclusion: pain score >3 on 0-10 VAS at triage, French/English speaking, limb with bony tenderness, swelling, limited range-of-movement or angulation <30deg.
  • Exclusion: allergy to opioids, NSAIDs or food colouring, critical illness, injury requiring orthopaedic reduction, trauma to >1 limb, social/physical abuse, cognitive deficit, chronic pain, analgesia in last 6h

Results: 83 patients enrolled from 279 eligible patients, 81 analysed; 40 in experimental and 41 in control arms. 47% had presented with fractures

Mean pain score at T1: experimental 5.9 +/- 1.7, control 5.7 +/- 1.3

Mean pain score at T3: experimental 4.0 +/- 2.4, control 4.1 +/- 2.0

Mean difference in pain scores between T1 & T3: -0.1 (95% CI -1.3 to 1.0), p=0.55

Authors’ Conclusions:

The addition of codeine to ibuprofen did not significantly improve pain management of children with a musculoskeletal trauma. Pain control provided by the medications remained suboptimal for most patients.

On the study design

Despite being a convenience sample, there are plenty of good methodological examples to be found in this paper. The use of allocation concealment (randomisation by computer generated blocks) and placebo, and careful preservation of blinding until after completion of the study are good examples of the role of study designers in reducing human influence on the results. The paper gives details as to how randomisation was carried out, which increases our faith in the strength of the methodology.

Arguably, a convenience sample reduces our ability to apply this data to our general PED population, however it could be countered that the majority of paediatric injury presentations occur between 09:00 and 21:00. In my clinical experience, the weighting does fall towards the evening, so perhaps an adjustment of the research nurse’s hours to reflect this might have been sensible.

There are a great number of inclusion and exclusion criteria, but these seem straightforward and sensible. The key to measuring the outcome (pain) is an ability to understand and communicate a pain score as per VAS, and many of the criteria are designed around ensuring that outcomes can be measured accurately in the sample. After all, for severely injured children we are likely to consider stronger opioids/opiates (such as diamorphine or fentanyl via the intranasal route), so if there is an analgesic role for codeine in PED it is likely to be in those children with mild-moderate pain.

It is worth noting that children requiring plaster immobilisation had to wait until the full 2hr study period had elapsed before their plaster was applied. I can understand that  this might cause a confounding effect, but I wonder if further studies might help us to quantify the benefit of splintage? Anecdotally from working with adults, plastering a fractured limb does provide relief. With increasing use of ultrasound to identify fractures at the bedside, should our emphasis be towards plastering earlier in the clinical encounter (and perhaps x-ray after plaster instead of before)?

What were the results and what does this mean?

The sample size calculation undertaken prior to the study required 28 children to be analysed in each arm at T3 in order to achieve power to detect a difference in means of 1.5. We can see this was achieved (31 patients remained in each arm at T3).

There was no statistically significant difference in mean pain scores between the two treatment arms at T3, which suggests no benefit in adding codeine to ibuprofen for these patients. Of note, one patient in the experimental arm complained of nausea. It would seem sensible to consider an alternative analgesic for co-administration.

What can we take from this paper into clinical practice?

Codeine is infrequently suggested for paediatric analgesia in my experience. As discussed above, if there is a role for its use it would likely be in those patients with mild-moderate pain. This is not supported by the findings of this study and as such it seems unlikely that anyone will be advocating the use of codeine for paediatric pain as yet.

More questions to ask

  • How can we best provide analgesia for children with limb injuries?
  • Does the role of robust splintage (e.g. plaster) compare favourably with analgesic agents?

Follow us on twitter: @PEMLit

7th December 2012: Validating the Difficult Intravenous Access Clinical Prediction Rule

 

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Lots of discussion about this already on Twitter – let’s take a look!071212

Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23187988

What is this paper about (what is the research question)?

How good is the Difficult Intravenous Access (DIVA) clinical prediction rule at identifying paediatric patients likely to require more than one attempt at intravenous cannulation.

Summary of the Paper

Design: prospective cohort study

Objective: validation of the DIVA score with derivation of test characteristics.

Test of interest: DIVA, a 4-part weighted clinical prediction rule. A score of 4 or more was thought to predict patients “50% more likely than the mean success rate to have a failed IV placement on the first attempt”

Success was placement of an intravenous cannula through which saline could be flushed without compromising the vein.

Primary outcome: test characteristics

Population: children aged 0-14 years requiring IV placement presenting to the ED of Mayo General Hospital in Ireland

  • Inclusion: children requiring IV placement
  • Exclusion: children requiring emergency treatment

Results: 500 children were recruited, 133 were younger than one year.

Mean failure rate was 22% – the authors state that 110 had a failed IV placement on first attempt (this doesn’t quite add up – see below).

151/500 had a DIVA score ≥ 4, of whom 57 (37.7%) had a failed IV placement on first attempt.

349/500 had a DIVA score <4, of whom 55 (15.8%) had a failed IV placement on first attempt.

For cutoff ≥4: sensitivity was 75.9%, specificity 51.8%, PPV 84.4%, NPV 37.7%.

Authors’ Conclusions:

This study validated the DIVA CPR in a population similar to that originally studied. Its acceptability and usefulness needs to be further accessed by health professionals involved in IV placement.

On the study design

The great thing about this study is that it appears highly generalisable – at least on the surface. All children who required IV access were eligible for inclusion between ages 0-14years and they were only excluded if IV was required as an emergency. The circumstances seem to reflect standard ED practice; topical local anaesthetic was used (although we don’t know which one) and doctors were limited in their attempts at cannulation before seeking help.

There are a few methodological issues though. Although we know a good amount about the population from which the sample was obtained, we don’t know how it was obtained – was it consecutive in a time frame? What time frame? Was it a convenience sample? Were these children selected at random? These factors might all affect the results – and we need to know them.

There are also some ethical issues – while there was a clear policy for seeking help after three failed attempts, it is unclear whether a second doctor was any more experienced/skilled at cannulation than the first. It would be nice to think that a senior doctor’s assistance was being enlisted. The study does have ethical  approval, but I wonder  whether this reflects standard rather than ideal practice.

We don’t know which local  anaesthetic was used; was there consistency here? Again, this might confound the results, or affect their external validity.

What were the results and what does this mean?

So, the results don’t add up, which is the first problem. Even if we take the authors’ word for the sums being right, the test characteristics are pretty useless. It’s easy to imagine that a ROC curve would have a pretty small area under the curve.

We also don’t have confidence intervals for the test characteristics. These are vital for gaining a true feeling for the usefulness of the data. There’s a great youtube resource explaining the importance of confidence intervals here.

What can we take from this paper into clinical practice?

Lots of questions! Much of the conversation on twitter asked whether this was even a relevant clinical question; @damian_roland wondered whether those who didn’t recognise the challenge of cannulation in infants – especially ex-prems – should be attempting cannulation.

There were also questions about what we should do with children for whom DIVA predicts difficult cannulation. Should we forego all cannulation attempts? Should we go straight for IO access? As much as I advocate timely IO as an approach for anyone with difficult access, the numbers don’t seem good enough to draw that sort of conclusion – but we do need to understand what we would want to  do with the findings before investing much more time in further validation of the rule.

What’s interesting is that in the paper children for whom failure was absolute went on to have enteral  rehydration by the NG route. There  is a cultural hesitancy around NG but it could certainly be argued that where it is possible it is  more physiological than intravenous hydration – so shouldn’t we be trying this before repeated IV attempts instead of afterwards? It also raises the question – who is deciding that these children need IV access? Is that also coming  from  doctors with one month of paediatric experience?

Lastly, we can reflect on the sites used for cannulation with greatest success. In my experience,  local anaesthetic is often applied by nursing staff to the antecubital fossa, particularly in the ED, whereas my preference is the dorsum of the hand. In the paper, the back of  the hand was used in 78.7% of successful cannulations. It would be interesting to  look at relationships between success  and site, considering where local anaesthetic  had been placed and whether doctor preference was expressed in advance of this.

More questions to ask

  • What do we want to use this data for in a clinical  context?
  • Has this paper simply highlighted a need to consider NG route for rehydration before IV?

Read the Twitter conversation here

Follow us on twitter: @PEMLit

30th November 2012: Diagnostic Value of Procalcitonin in Well-Appearing Young Febrile Infants

 

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Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23109682

What is this paper about (what is the research question)?

How good is procalcitonin at predicting the presence of serious bacterial infection in children – and in particular, those aged ≤ 3months of age?

Summary of the Paper

Design: Retrospective multicentre diagnostic trial.

Objective: to assess the value of procalcitonin in diagnosing serious bacterial illness and in particular invasive bacterial infections in well-appearing infants with “Fever Without Source” (known as pyrexia of unknown origin in the UK)

Reference standard: serious bacterial infection, defined as isolation of pathogen from blood, CSF, urine or stool, or invasive bacterial infection – isolation of bacterial pathogen from blood or CSF.

Test of interest: procalcitonin measured using quantitative immunochemiluminesence assay.

Population: Retrospective inclusion of cases from 5 Spanish and 2 Italian PEDs

  • Inclusion: infants ❤ months of age with fever of unknown origin for whom procalcitonin was measured and blood culture performed.
  • Exclusion: patients in whom source of fever could be identified, patients classed as appearing unwell at presentation, patients who were afebrile without thermometer confirmation of fever prior to attendance, patients in whom procalcitonin was not measured, not recorded or blood culture not obtained.

Results: 1531 infants ❤ months of age with fever of unknown origin identified over 3 year period (exact recruitment period variable by centre) across three centres. 1112 included for analysis.

26% were diagnosed with serious bacterial infection, 2.1% with invasive bacterial infection.

Multivariate logistic regression analysis was performed for risk factor variables. Only PCT ≥ 0.5ng/mL was an independent risk factor for invasive bacterial infection: OR 21.69 (95% CI 7.93-59.28), with an area under the curve for SBI 0.739 (95% CI 0.702-0.776) and for IBI 0.825 (95% CI 0.698-0.952).

Authors’ Conclusions:

Among young infants with fever without source, procalcitonin is a better marker than CRP for identifying patients with invasive bacterial infection and also seems to be the best marker for ruling out invasive bacterial infection.

On the study design

We have discussed previously the issues of retrospective design. There are issues here about the inclusion and exclusion criteria; many are reliant on subjective variables such as “appearing well”. Arguably this has inherent reliability problems and we could argue the accuracy of physician assessment is dependent on exposure to paediatric patients and experience levels.

Inclusion of patients for whom both procalcitonin and blood culture were performed seems to instinctively select out a population for whom there are red flag signs (or symptoms) of underlying illness, even though the subjects were considered to appear “well” and no source of fever was apparent on examination.

The issue of reference standard is important too. We know that some children are undoubtably septic but no organism is definitively cultured, despite best efforts. Absence of diagnostic culture does not equate to absence of serious or invasive bacterial infection.

What were the results and what does this mean?

The results here are a little complicated, so bear with me.

It’s difficult to even produce a 2×2 table; the raw data doesn’t seem to be there. Procalcitonin <0.5ng/mL has a negative LR of 0.66 (95% CI 0.59-0.73) which implies that the odds of a patient with a procalcitonin level <0.5ng/mL having underlying serious bacterial illness is 0.66 times the odds that the patient with a procalcitonin above this level has underlying serious bacterial illness. The LR of a negative procalcitonin (<0.5ng/mL) for invasive bacterial illness is even more compelling: 0.25 (95% CI 0.12-0.55).

As we have seen on other papers, the confidence intervals are quite wide.

As for the predictive power of a raised procalcitonin, where the level was ≥2.0ng/mL the LR was 7.12 for serious bacterial illness (95% CI 4.52-11.21) and 11.14 for invasive bacterial illness (95% CI 7.81-15.89). So the odds that a patient with a raised procalcitonin has underlying serious bacterial illness is 7.12 times the odds that a patient with a raised calcitonin doesn’t have serious bacterial illness, and for invasive bacterial illness the odds of disease presence are 11.14 times the odds that there is no disease when the procalcitonin is ≥2.0ng/mL

What can we take from this paper into clinical practice?

Procalcitonin seems to be a useful indicator that underlying bacterial illness might be present (≥2.0ng/mL) or absent (<0.5ng/mL).

Looking at the area under the ROC curves, it doesn’t appear that procalcitonin is quite good enough to definitively rule in or out the presence of underlying bacterial illness. The retrospective design and tight inclusion criteria also limit the extrapolation of these results to the undifferentiated PED population.

More questions to ask

  • How useful would procalcitonin be when tested prospectively in an undifferentiated PED population – including those who appear “sick”?
  • What do we clinically do with patients whose procalcitonin falls between these two cutoff points?
  • How would the results be affected by a standardised investigative approach to infants with febrile illness without clear source?

Follow us on twitter: @PEMLit

23rd November 2012: Early Lactate Testing in Undifferentiated Paediatric SIRS

Where can I find this paper?

http://www.ncbi.nlm.nih.gov/pubmed/23167859

What is this paper about (what is the research question)?

Does an ED measurement of hyperlactataemia (serum lactate ≥ 4.0mmol/L) predict increased risk of organ dysfunction within 24h?

Summary of the Paper

Design: single-centre prospective observational cohort study

Objective: to ascertain whether an ED serum lactate of ≥4.0mmol/L predicts risk of organ dysfunction within 24h in paediatric patients presenting with systemic inflammatory response syndrome (SIRS)

Intervention: point-of-care venous lactate measurement

Primary outcome: organ dysfunction within 24h of triage time, classified following International Paediatric Sepsis Consensus Conference definitions.

Population: convenience sample of patients presenting to ED of tertiary children’s hospital over 1 year (recruitment occurring 17/24h per day)

  • Inclusion: patients <19 years old with temperature >38.5 or <36 and HR>2 standard deviations above normal for age, undergoing phlebotomy or CVC access as part of their care
  • Exclusion: patients transferred from other institutions, patients with known inborn errors of metabolism, lactate not measured within 15mins of IV therapy initiation.

Results: 239 eligible subjects enrolled (missed eligible rate 36%), of whom 8% were admitted to an intensive care unit.

Mean lactate was 2.0 (+/- 1.2) mmol/L. 8% of subjects had hyperlactataemia. 5% of subjects had organ dysfunction within 24h; 4% of the low lactate population, 22% of the hyperlactataemic population.

Hyperlactataemia had an LR+ of 5.0 (95% CI 1.9-13.0) for organ dysfunction within 24h, sensitivity 31% (95% CI 13-58%), specificity 94% (95% CI 90-96%).

The relative risk of lactate ≥ 4.0mmol/L was 5.5 for 24-hr organ dysfunction

Authors’ Conclusions:

Serum lactate measurement identifies a population at higher risk for severe outcomes than the broader Paediatric ED population with fever and tachycardia and would be a useful addition to clinical assessment in paediatric sepsis clinical and research protocols.

On the study design

As with so many papers, the convenience sampling presents a potential problem in extrapolating this data to our own EDs. While convenience sampling is common, practical and understandable, it does impact the external validity.

To their credit, the authors have been honest about this, giving us a “missed inclusion” rate of 36%. This suggests that greater than 1/3 paediatric patients presenting with two SIRS criteria do so in 29% of the 24h period. We can only imagine how including these patients would affect the results.

The inclusion criteria are interesting too; I would suspect that many more than 239 patients present to an average PED with fever and tachycardia in 12/12 (particularly as we know that the annual attendance is around 80,000). This means that a large number of these patients did NOT have blood tests. This, of course, represents our standard practice (we don’t bleed every child with a temp and tachycardia), but it means we can only really consider the value of lactate measurement in those children whom we already deem to be systemically unwell. It would also be useful to know if a capillary lactate could help to identify those patients for whom we are not sure whether blood tests are necessary.

What were the results and what does this mean?

Despite small numbers, the study was adequately powered by their own calculation. The relative risk of lactate ≥4.0mmol/L for 24-hr organ dysfunction means that patients with an initial lactate above 4.0mmol/L have 5.5 times the risk of 24-hr organ dysfunction as those with a lactate below 4.0mmol/L. They also had 2.2 times the risk of serious bacterial infection, 4.6 times the risk of positive culture and 4.4 times the risk of ICU admission.

The low sensitivity sensitivity (31% (95% CI 13-58%)) tells us that we cannot be reassured by an initial normal lactate (we are unable to use it to “rule out” serious illness), but the specificity is  reasonable at 94% (95% CI 90-96%) – raised lactate should raise our concern. Clinically, a high specificity is more useful to us as arguably it is more important to reliably rule-in serious illness.

What can we take from this paper into clinical practice?

If we are taking bloods in children in the ED because they have signs of SIRS, a venous lactate may help with risk stratification by predicting those more likely to require antibiotics and organ support. It is probably worth taking one if you are taking bloods, but a normal lactate is not reassuring. It is not yet clear how this applies to children about whom we are unsure as to the need for blood tests.

More questions to ask

  • How would the results differ if we obtained a venous (or capillary) lactate from  all paediatric patients meeting the two SIRS criteria used in this paper (temperature and heart rate)?
  • How would results be affected  if we included children recruited around the clock rather than a convenience sample?

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