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.

Surviving Sepsis Campaign International Guidelines

Cite this article as:
Damian Roland. Surviving Sepsis Campaign International Guidelines, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.23460

The lens with which you view sepsis is dependent on the environment and emotion in which you associate the term. For a parent, this may be the spectrum from having never heard the term before “Your child is well enough to go home, we’ve ruled out sepsis and other serious conditions” to the anguish of being told, “I’m afraid your child died of sepsis“. This spectrum remains equally wide for health care professionals. A family doctor or general practitioner may never see a case of confirmed sepsis, and an emergency clinician can potentially go years between seeing a truly shocked child. An intensivist, however, may deal with the consequences on a weekly basis. Even in the last month, we have seen two papers from the same publishing group; one highlighting the global burden of sepsis and the other challenging the current hype surrounding its recognition and management.

Regardless of your viewpoint, the publication of the Surviving Sepsis campaign’s international guidance will have been of interest.

 

Weiss, S.L., Peters, M.J., Alhazzani, W. et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 46, 10–67 (2020). https://doi.org/10.1007/s00134-019-05878-6

 

It is important to recognize two features of this publication which should carry an important health warning in its interpretation.

The first is that the authors are clear that they are focusing on severe sepsis or septic shock. While in adult practice definitions have changed, these have not been formalized or ratified for children:

 

“For the purposes of these guidelines, we define septic shock in children as severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion) and “sepsis-associated organ dysfunction” in children as severe infection leading to cardiovascular and/or non-cardiovascular organ dysfunction.”

 

The authors clearly recognize that the absence of a clear definition of paediatric sepsis is challenging health care providers and organizations. The group has steered away from suggesting management options in the ‘pre-sepsis’ group i.e. those children with potential infections that may result in sepsis and have physiological instability but without organ dysfunction. They suggest that management practices for this group aren’t radically different, however:

 

Even though these guidelines are not intended to address the management of infection with or without SIRS when there is not associated acute organ dysfunction, we recognize that sepsis exists as a spectrum and some children without known acute organ dysfunction may still benefit from similar therapies as those with known organ dysfunction

 

The second is that this is a consensus document. It is neither a systematic review nor a clinical practice guideline (in a local hospital sense). It comprises the opinions of an expert group of clinicians (49 in fact) from a variety of international settings using the best available evidence. The publication is essentially a list of recommendations. This approach is valid in situations where evidence may be heterogeneous and that randomized controlled trials can not be performed for all possible permutations of clinical practice. As with all things in science, however robust the data is, it still needs interpreting and that interpretation is subject to all manner of explicit and implicit bias.

 

The panel supports that these guidelines should constitute a general scheme of “best practice,” but that translation to treatment algorithms or bundles and standards of care will need to account for variation in the availability of local healthcare resources.

 

Without becoming meta it’s important that this blog itself needs a health warning. It’s an interpretation of an interpretation of evidence.

So the big-ticket items

1. A child was defined as beyond 37 weeks gestation and up to 18 years old.

2. They apply to children with severe sepsis or septic shock as defined by the 2005 International Pediatric Sepsis Consensus Conference or inclusive of severe infection leading to life-threatening organ dysfunction.

2005 definition:

  • greater than or equal to two age-based systemic inflammatory response syndrome (SIRS) criteria
  • confirmed or suspected invasive infection, and cardiovascular dysfunction
  • acute respiratory distress syndrome (ARDS), or greater than or equal to two non-cardiovascular organ system dysfunctions

Septic shock was defined as the subset with cardiovascular dysfunction, which included hypotension, treatment with a vasoactive medication, or impaired perfusion.

3. Panel members were selected through recommendations from chairs and vice-chairs of the 12 worldwide member organizations. Each panel member was required to be a practicing healthcare professional with a focus on the acute and/or emergent care of critically ill children with septic shock or other sepsis-associated acute organ dysfunction. There was lay representation and the final membership was felt to be demographically diverse with regard to sex, race, and geography.

4. The panel was assisted by various methodological experts and split into six groups

  • recognition and management of infection
  • hemodynamics and resuscitation
  • ventilation
  • endocrine and metabolic therapies
  • adjunctive therapies
  • review research priorities in pediatric sepsis

5. A list of critical questions was developed in the PICO format (Population, Intervention, Control, and Outcome) which was then rigorously searched for by a specialist medical librarian and the resulting literature assessed according to GRADE criteria a well-recognized methodology for systemically presenting summaries of evidence.

6. Following discussion and debate recommendations would be made:

 

We classified recommendations as strong or weak using the language “We recommend…” or “We suggest…” respectively. We judged a strong recommendation in favor of an intervention to have desirable effects of adherence that will clearly outweigh the undesirable effects. We judged a weak recommendation in favor of an intervention to have desirable consequences of adherence that will probably outweigh the undesirable consequences, but confidence is diminished either because the quality of evidence was low or the benefits and risks were closely balanced.

 

The paper goes into considerable detail (which is why it is 55 pages long) into the rationale behind the recommendations. They are all summarised in the appendix (commencing page e102). It is beyond the scope of this blog to explore all the recommendations in detail, and it is important that health care providers read the paper itself. The following highlights some of the areas which may prompt debate or query.

 

‘Screening’ remains in

For those in emergency and acute care, this recommendation may have come as a surprise given a large amount of anecdotal feedback and experience suggesting that current screening mechanisms for the un-differentiated child are neither specific nor sensitive. It is worth nothing again the panel was looking at severe sepsis or shock and the evidence for ‘bundles’ of care i.e. targeted or mandated treatments once recognized is relatively robust. There is a further section on protocols/guidelines for treatment but it may have been useful to separate the afferent limb (recognition) from the efferent limb (response) in relation to collated evidence. This is important as the evidence for ‘bundles’ is cited under screening, with minimal evidence of screening approaches alone put forward (or to be fair to the panel perhaps of insufficient quality to make a judgment on).

Although subtle I think the panel recognized how important local buy-in is in relation to quality improvement. Of note, there is nothing on national guidance for recognizing sepsis. They also highlight how blindly integrating screening with any other scoring system may not be as beneficial as believed.

Ultimately no one particular screening system is recommended.

 

There is no target lactate

There appears to be a palpable sense of regret that the evidence didn’t support any particular threshold for lactate. Despite evidence of rising mortality with increasing lactate, the panel was not able to determine a specific level.

However, no RCTs have tested whether initial or serial measurement of blood lactate directly informs evaluation and/or management in children. Lactate levels should, therefore, be interpreted as a part of a more comprehensive assessment of clinical status and perfusion.

 

Take blood cultures but don’t delay treatment to obtain them

Appreciating this isn’t a particularly scientific response, but well, duh.

 

One hour time to treatment for those in shock but up to three hours without it. 

This is the potential game-changer from this body of work. While the evidence shows a temporal relationship between the administration of antibiotics and outcome in severe sepsis some pooled data demonstrated that it was unlikely the hour alone made the difference. Given the numerous papers showing a linear relationship between time to administration and outcome the ‘golden hour” was maintained. In the absence of shock, the panel felt, based on data showing a three-hour threshold effect, this would be a reasonable time point. This will be a welcome relief for those working in areas where there are associated penalties for not reaching the hour window and hopefully will remove some of the gaming associated with this target.

 

Broad spectrums antibiotics, but narrow when pathogens available

Little controversy here. The panel highlight that 48 hours should be the maximum time that is allowed to pass before re-evaluation in the absence of culture growth rather than a standard time to elapse.

If no pathogen is identified, we recommend narrowing or stopping empiric antimicrobial therapy according to clinical presentation, site of infection, host risk factors, and adequacy of clinical improvement in discussion with infectious disease and/or microbiological expert advice.

There are a number of recommendations on immunocompromised children and source control which appear pragmatic.

 

Bolus if intensive care available, if not then don’t unless documented hypotension

In units with access to intensive care, 40-60ml/kg bolus fluid (10-20ml/kg per bolus) over the first hour is recommended. With no intensive care, and in the absence of hypotension, then avoiding bolus and just commencing maintenance is recommended. It is not clear how long access to intensive care has to be to switch from fluid liberal to restrictive.

**Post-publication note (13/02/20): A more correct description of no intensive care would be “in health systems with no access to intensive care”. The guidance states, “For children with septic shock without signs of fluid overload in low-resource settings where advanced supportive and intensive care is not available, the panel recommends against bolus fluid administration,”. This question is raised in the comments section below as for units in without intensive care on site but it will resourced health systems then ‘access’ to intensive care should be assumed**

For purposes of this weak recommendation, hypotension can be defined as:

 

The panel suggests crystalloids, rather than albumin, and balanced/buffered crystalloids rather than 0.9% saline. They recommend against using starches or gelatin.

 

Use advanced haemodynamic variables, not bedside clinical signs in isolation

The evidence didn’t support a target mean arterial blood pressure but suggested avoiding using clinical signs to differentiate into cold and warm shock. No one monitoring approach was advised but included cardiac output, cardiac index, systemic vascular resistance, and central venous oxygen saturation.

 

Intensive care vasoactive and ventilation management is given but acknowledged as weak recommendations 

There is a list of suggestions regarding vasoactive infusion and ventilatory strategies that are very specific to intensive care management. While a number of recommendations are given (epinephrine rather than dopamine for septic shock for example) these are generally based on the panels summation of weak evidence.

There are further suggestions on corticosteroid management, nutrition, and blood products which will be of interest to those in intensive care and anaesthetic settings.

 

Summary

This is a very rich piece of work that is well structured and easy to read (even if you are not an expert on a particular field of practice). For most paediatricians there is unlikely to be an immediate change in practice but the softening of antibiotic time to delivery in the non-shocked child and emphasis of local review of sepsis incidence and performance will be welcome. How these filter into national guidance will be determined country by country but it is unlikely that radically different views can be drawn from the available evidence. What is still sorely needed is a working definition for the non-hypotensive child with sepsis (or an acknowledgment that perhaps this isn’t really a clinical entity…)