Currie, V. The 49th Bubble Wrap, Don't Forget the Bubbles, 2021. Available at:
https://dontforgetthebubbles.com/the-49th-bubble-wrap/
With millions upon millions of journal articles being published every year it is impossible to keep up. Every month we ask some of our friends from PERUKI (Paediatric Emergency Research in UK and Ireland) to point out something that has caught their eye.
Article 1: The associations between initial serum pH value and outcomes of paediatric out-of-hospital cardiac arrest
Okada A, Okada Y, Kandori K, Nakajima S, Okada N, Matsuyama T, Kitamura T, Hiromichi N, Iiduka R. Associations between initial serum pH value and outcomes of pediatric out-of-hospital cardiac arrest. Am J Emerg Med. 2021 Feb;40:89-95. doi: 10.1016/j.ajem.2020.12.032. Epub 2020 Dec 17. PMID: 33360395.
What’s it about?
This paper reviewed the association between initial pH, obtained via intra-arrest VBG, and patient outcomes to evaluate if pH can be used to prognosticate in paediatric out of hospital cardiac arrest.
The authors reviewed a large, multicentre, prospective register of out-of-hospital cardiac arrests in 87 hospitals in Japan. They included paediatric out-of-hospital cardiac arrest patients younger than 16 between June 2014- December 2017 (458 patients included in the analysis – however over 35,000 listed in the registry). The primary outcome was 1-month survival. They divided the patients into four groups (based on initial pH on blood gas) and compared this to the patient’s ultimate outcome.
Interestingly, the median age of the patients was one year of age. Just over 6 in 10 of the patients were male. In 7 out of 10 patients, the first monitored rhythm was asystole. Cardiogenic arrest occurred in 4 out of 10 patients.
Mortality, and survival with good neurologic function, were lookd for. The overall survival rate at one month was just over 1 in 10 patients. In the group with pH > 6.82 survival rate was around 4 in 10 patients. However, with a pH< 6.47, thesurvival rate was 1 in 100 patients.
Of particular interest, in the entire study population of 458 patients, there were no patients who survived with good neurological function with a pH <6.8.
Why does it matter?
Deciding when to stop resuscitation in a paediatric cardiac arrest can be difficult. Guidance is sparse and there are no universally recommended measures to help providers decide when to stop resuscitative measures. This is a stark contrast to adult cardiac arrest management where there are many validated termination of resuscitation rules based on measurements such as end-tidal CO2 s.
This is the first study to assess the association between pH and prognosis in paediatric out-of-hospital cardiac arrest. It presents robust evidence to support an objective, easily obtained measure that can be used to assist decision making around the termination of resuscitation. Important exclusions in this study were patients where resus was not attempted at a hospital, unknown age, traumatic or arrest secondary to hanging and those with no pre-hospital data.
This is an exciting paper providing guidance in an area sorely lacking any previous data. It gives providers a valuable tool that can substantially assist when making a difficult decision.
Clinically Relevant Bottom Line:
In out of hospital paediatric cardiac arrest, according to this study, no patients with a pH <6.8 survived with a neurologically favourable outcome. Survival in general was significantly lower in patients with an initial pH <6.8.
Reviewed by: Sean Croughan
Article 2: Should we be using focused cardiac ultrasound to guide therapy in children with sepsis?
Arnoldi s, Glau CL et al. integrating focused cardiac ultrasound into Pediatric septic shock assessment. Pediatr Crit Care Med. 2021 mar 1;22(3):262-274
What’s it about?
This paper looks at whether the integration of FCU (focused cardiac ultrasound) in clinical assessment of children with sepsis would alter clinician’s evaluation of their haemodynamic characteristics.
The authors conducted a retrospective, observational study from January 2014 – December 2016 in a large PICU in America. They reviewed 74 PICU patients who received FCU within 72 hours of sepsis pathway initiation. Assessment by clinicians prior to FCU was compared to assessment after FCU in 46 patients, to determine if there was a difference in the haemodynamic characterisation of patients.
They demonstrated that incorporation of FCU changed the clinician characterisation of haemodynamic assessment made prior to FCU in more than 2 out of 3 of cases. The most common new finding identified post-FCU was myocardial dysfunction in (7 out of 22) cases. The most commonly ruled-out physiologies by clinician after FCU performance were obstructive physiology (5 in 8 cases), fluid responsiveness (13 in 26 cases).
Why does it matter?
Sepsis in children continues to be one of the leading causes of mortality and morbidity worldwide. Most children who die of sepsis suffer from refractory shock and/or multiple organ dysfunction within the initial 48 -72 hours of treatment, thus demonstrating the need for early and targeted interventions.
The previous method of classifying patients as having either ‘warm shock’ or ‘cold shock’ to guide therapy has been demonstrated to have poor correlation with cardiac function and systemic vascular resistance, and has not led to improved outcomes. It is now recommended that more advanced techniques such as focused cardiac ultrasound (FCU) be used alongside clinical assessment to identify haemodynamic status and direct therapy. This is already widely the case in adult practice and algorithms have been created for its integration into patient management.
Although this is a small study, it makes us think about the use of cardiac ultrasound alongside clinical assessment of children with sepsis in order to understand the haemodynamic characterisation of these patients.
This may be particularly useful in relation to fluid responsiveness, as half of the children who were thought to be fluid responsive pre-FCU, were found not to be after a FCU was performed. We know that children with sepsis often receive significantly more fluid per kilogram than adults which is associated with worse outcomes.
Clinically Relevant Bottom Line:
FCU, when incorporated into shock assessment, has the potential to identify myocardial dysfunction earlier and could result in reduced fluid administration as well as more targeted therapy based on haemodynamic status. However, further work is needed to determine how this can be used within paediatric practice.
Reviewed by: Laura Duthie
Article 3: Don’t forget the planet
Di Cicco, M.E., Ferrante, G., Amato, D., Capizzi, A., De Pieri, C., Ferraro, V.A., Furno, M., Tranchino, V., La Grutta, S. (2020) Climate Change and Childhood Respiratory Health: A Call to Action for Paediatricians. Int J Environ Res Public Health, Vol 24;17(15):5344
What’s it all about?
The authors conducted a systematic review looking at papers which examined the connection between respiratory illnesses in children aged 0 – 18 years. Keywords used separately and in combination were (allergic rhinitis, rhinitis, asthma, bronchitis, pneumonia, infections) and key environmental phrases (climate change, pollution, particulate matter, ozone, nitrogen dioxide, allergen, pollen). There was no limitation on the date of paper or country of origin.
Whilst much of the research at this stage is not completely conclusive key points from the review include:
- Several studies from different countries found a connection between the increased prevalence of rhinitis and asthma, as well as the frequency of symptoms with increased global temperatures, which has changed many plant species’ lifecycles and led to longer pollen seasons
- Positive correlations between the incidence of pneumonia and other acute respiratory tract infections in the context of increased extreme weather events such as heatwaves, fires and floods
- Positive associations between the increased relative humidity and increased activity of respiratory viruses such as respiratory syncytial virus
Why does it matter?
Climate change is the long-term shift in weather conditions (temperature, humidity, winds and extreme weather events) and is often talked about in regards to protecting our wildlife or preventing further damage to our oceans and forests. It is less talked about when considering the impact on our own health. A child born in 2020 will live in a world that is more than 4 degrees warmer than the pre-industrial average, and subsequently will be at greater risk of a variety of acute illnesses as well as long term health consequences.
The Bottom Line:
More research needs to be done to accurately define the burden of climate change on our health. In the interim, we can all be environmental champions, from making changes in our own lives to reduce our carbon footprint as well as educating and influencing our colleagues and patients to do the same.
…And for those with spare time; conducting research into the direct effects of climate change on specific health conditions along with contributing to government policies to create change at a higher level and reducing the carbon footprint of our healthcare systems are excellent places to start!
Reviewed by: Tina Abi Abdallah
Article 4: Domo arigato, Mr Roboto
Littler BKM, Alessa T, Dimitri P, et al Reducing negative emotions in children using social robots: systematic reviewArchives of Disease in Childhood Published Online First: 08 March 2021. doi: 10.1136/archdischild-2020-320721
What’s it about?
The paper looks at a number of studies that have used social robots in paediatric outpatient settings to interact and provide multi-sensory experiences to patients. The author postulates that using social robots provides better interaction and distraction for children, thus reducing anxiety and distress during the visit.
This systematic review managed to find ten studies that used social robots ranging from humanoid-based robots to ones simulating toy bears, dinosaurs and seals. The robots interact verbally and physically, and can respond to patient cues and tactile stimulation. They were used before or during the intervention. The studies included randomised controlled trials, exploratory trials, pilot and an observational study, with patient numbers varying from 2 to 73 (320 in total).
Why does it matter?
For lots of children a visit to the hospital can be a stressful and anxiety inducing event. There has been research to suggest that social robots have a positive impact on supporting adults with dementia and in children with autism they have been a useful tool in conducting therapy. The outcomes of this study were measured by observation, and by recording levels of distress, anxiety, pain and emotion using a variety of behavioural questionnaires. Overall, the feedback from the studies showed positive engagement from patients with their robots, reducing negative emotions, distress and pain.
The bottom line
There is promising data to suggest that robots may improve the experience of children in the healthcare environment. However, the evidence is weak due to the nature of the studies, lack of uniformity in the measurements, and low patient numbers. More research is needed on this topic to be able to really change practice but this sci-fi intervention may well become a reality in the not so distant future.
Reviewed by: Laura Riddick
Article 5: Children visiting the Paediatric emergency department during Ramadan
Sawaya,R., Wakil, C., et al (2021) Pediatric emergency department utilisation during Ramadan: a retrospective cross- sectional study. Archives of Disease in Childhood 2021;106:272-275.
What’s it about?
This study looks to investigate the impact of Ramadan on patient characteristics, diagnoses and metrics in the paediatric emergency department (PED). There is limited data on how Ramadan impacts paediatric ED’s.
Why does it matter?
The authors looked at patient and illness characteristics as well as PED metrics including peak patient load, presentation timings, length of stay, time taken to order tests, receive samples and reporting of results to see how these were affected during the months of Ramadan and those before and after.
This is a retrospective cross-sectional study on paediatric patients from 0 – 18 years presenting to a PED tertiary centre in Lebanon. Data was collected from all PED visits with any complaint at any time during Ramadan and the months (30days) before and after in 2016 and 2017. A bivariate analysis was performed between the Ramadan and non-Ramadan groups. The main outcomes were illness severity, chief complaints, final diagnoses, PED metrics including peak patient load, presentation timings, length of stay, and PED efficiency metrics such as time to order tests, times to samples being received and reported. 5711 patients were included and 1672 of these presented during Ramadan. There was no significant difference between age, gender or illness severity between the Ramadan or non-Ramadan group. This study found a significant difference in the number of GI complaints during Ramadan (39%) compared with the non-Ramadan group (35%).
Trauma related complaints increased during Ramadan (3 in 100) vs (2 in 100) in non-Ramadan periods. Especially during the non-fasted periods of Ramadan (4 in 100) vs (2 in 100) during the fasted period of Ramadan. The number of daily visits during Ramadan (28.3) was reduced compared with non-Ramadan attendances (31.5). The Ramadan group did not have to wait longer for tests to be ordered or to have samples collected.
This study was a single centre- and the charts that were reviewed did not have information on the patients individual fasting status. This would be interesting to see if the patient’s individual status affected diagnosis. The team used months immediately before and after Ramadan to reduce the confounding effects of seasonal bias.
Clinically Relevant Bottom Line:
This study revealed that there were some changes in GI and trauma presentations during the Ramadan period. There was also a reduction in cases presenting in this centre- this could help to influence staffing during this time if the patient population reflected that of the population in this study.
Reviewed by: Vicki Currie
If we have missed out on something useful or you think other articles are absolutely worth sharing, please add them in the comments!
That’s it for this month. Many thanks to all of our reviewers who have taken the time to scour the literature so you don’t have to.
All articles reviewed and edited by Vicki Currie
Febrile Infection-Related Epilepsy Syndrome (FIRES)
Jessica Archibald and Catherine Murphy. Febrile Infection-Related Epilepsy Syndrome (FIRES), Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.32716
An 8-year-old presents to the emergency department following a first seizure episode. They had a witnessed generalised tonic-clonic seizure that morning lasting approximately 60 seconds and remain post-ictal. They have a history of being non-specifically unwell yesterday with subjective fever, lethargy and a mild headache. They have no significant past medical history and no family history of seizures. The examination is unremarkable. Whilst in the emergency department they have a further two self-terminating generalised tonic-clonic seizures.
Febrile Infection-Related Epilepsy Syndrome (FIRES) is a rare epileptic encephalopathy that results in prolonged refractory status epilepticus in previously well patients.
Presenting Features
FIRES typically presents in children between the age of 3 to 15 years, with intractable status epilepticus, 2 to 10 days post a febrile illness. The preceding illness is most commonly an upper respiratory tract infection or gastroenteritis. Fevers may have resolved prior to the onset of the acute phase of the condition.
The acute phase of the illness is characterised by frequent seizures, rapidly progressing to status epilepticus. Although the seizures are initially focal in nature, they may evolve into secondary generalised seizures. The acute phase can be prolonged, lasting from weeks to months. An association with rash, liver derangement and arrhythmia has been noted in the literature. There is no latency period.
The chronic phase is denoted by refractory epilepsy, resulting in seizures that may cluster every 2 to 4 weeks. This is often associated with severe neurological impairment and cognitive decline.
FIRES had previously been thought to only occur in children, and New-Onset Refractory Status Epilepticus (NORSE) only in adults, however this theory has been disproven. Although FIRES is more prevalent in children, it has been known to also occur in adults. As such, FIRES is now considered a subtype of NORSE, characterised by a preceding febrile illness. It has previously been known as Acute Encephalitis with Refractory, Bepetitive Partial Seizures (AERRPS) and Devastating Epilepsy in School-age Children (DESC).
Aetiology
The aetiology of FIRES in unknown and as such the pathophysiology remains unclear.
One theory is that FIRES is a form of severe infectious encephalitis, but as yet no infectious agent has been identified, and the refractory nature of the seizures is atypical of encephalitis. Another hypothesis suggests FIRES is the result of an immune response, however, there is not enough evidence to support this theory.
A case identifying anti-GABA A receptor antibodies in the CSF of a patient who presented with severe refractory status epilepticus associated with a fever led to speculation that the condition may be autoimmune-mediated. Again this has not been proven and the case may have been an exception rather than a rule.
Other theories include genetic associations and potential links with metabolic disease, but as yet a cause has not been identified.
Diagnosis and Differentials
The diagnosis of FIRES is essentially clinical, as FIRES is a cryptogenic illness. The work up is initially general, and focused on the exclusion of other treatable causes, such as infectious or autoimmune encephalitis.
A detailed history will identify the preceding febrile illness, and would be focussed on the identification of risk factors for other causes for the presentation, including exposure to animals, drugs and toxins, recent foreign travel and immunosuppression.
Blood sampling will be used to identify an infectious cause for the presentation, through full blood count, blood cultures and a screen for atypical infective agents. Lumbar puncture should be performed for CSF sampling in order to investigate bacterial, viral, fungal or autoimmune causes. CSF may show a mildly elevated white cell count in those with FIRES.
EEGs may show a generalised slowing, in keeping with an encephalopathic picture, but do little in the way of distinguishing between other causes of seizures. However, they are useful in guiding treatment and identifying non-convulsive seizures.
Initial MRI imaging is often normal, however, follow up imaging has been associated with devastating changes. Early MRI, in the first weeks of the acute illness, has shown swelling of the mesial temporal structures and increased T2 weighted signal. Follow up MRI, greater than 6 months after onset, may be associated with bilateral mesial temporal atrophy and increased T2 weighted signal. It should be noted that MRI may be normal in 50% of cases.
Differentials to consider are Dravet Syndrome, which presents with a febrile illness associated with status epilepticus, though this tends to present within the first year of life. Also Alper’s Disease, which presents with refractory seizures in previously well children, and is often associated with liver disease.
The patient is loaded with levetiracetam (40mg/kg) as per hospital guidelines, and admitted under paediatrics locally. A CT head is unremarkable and bloods show mild LFT derangement with normal inflammatory markers. They are treated empirically with intravenous cefotaxime and aciclovir. Later that afternoon they develop a fever of 38.3.
The GCS fluctuates between 11 to 13 with no full recovery to baseline until later that evening. Following two focal seizures the next afternoon, they are transferred to the local tertiary centre for further investigation and management.
Initial Management
Initial management involves treating the seizure, and more often status epilepticus. Local hospitals have their own guideline for managing status epilepticus but the first line is typically benzodiazepines (lorazepam, diazepam, midazolam, clonazepam). Second-line treatment is standard anti-convulsants (levetiracetam, phenytoin, phenobarbitone, sodium valproate), however, FIRES does not typically respond to these medications even in high doses.
The seizure pattern in FIRES is often resistant to multiple anti-epileptics. Alternative treatment options have to be sought although there is limited evidence as to the optimal treatment.
Long-term Management
There is limited data on the treatment of FIRES, however, they all conclude the seizures are very difficult to manage and often require polytherapy. Some of the alternative treatment options include drug-induced burst-suppression comas, immunotherapy, a ketogenic diet, vagus nerve stimulation, therapeutic hypothermia and intravenous magnesium sulfate. The most commonly used and researched options are discussed below.
Burst suppression coma
Burst suppression coma induction is viewed as standard care for refractory status epilepticus. If first and second-line treatments fail the next option involves high doses of anti-convulsants along with anaesthetic agents, for example, an infusion of midazolam, barbiturates or propofol. Unfortunately when the anti-convulsants are weaned the seizures tend to reoccur. Prolonged burst suppression coma has been associated with a significantly worse cognitive outcome and poorer prognosis.
Immunotherapy
Immunotherapy has been trialled due to the suspected role of inflammation in the pathogenesis of FIRES. High dose steroids, intravenous immunoglobulin and plasmapheresis have all been used. There is limited evidence to suggest a beneficial role in the management of refractory epilepsy. A large-scale Japanese study described 2 out of 12 patients responding to steroids, although there is not enough evidence to support this as a treatment option. Treatment with immunotherapy is often associated with significant side effects
Anakinra is a recombinant and modified human interleukin-1 receptor antagonist protein. Recent evidence has shown it to be an effective and promising treatment option in patients with FIRES, though relapse has been reported after withdrawal. It has been shown to decrease the duration of mechanical ventilation and hospital length of stay, and possibly seizure reduction. Future studies are required to understand the optimum dosing regime and safety of anakinra.
Ketogenic diet
A ketogenic diet is a high fat, adequate protein and low carbohydrate diet aimed at imitating the body’s fasting state. The body, therefore, metabolises fat for energy. The early introduction of the ketogenic diet has shown to be beneficial in the management of FIRES in uncontrolled trials. It has been suggested that the ketogenic diet may have an anti-inflammatory, as well as an anti-convulsant effect. Some reports suggest it may also have a positive effect on long term cognition. Currently, it is one of the only management options shown to be effective. Future controlled studies are needed to prove this efficacy.
Vagus nerve stimulation
Vagus nerve stimulation (VNS) involves the implantation of an electrode that produces intermittent electrical stimulation into the left cervical vagus nerve. Case reports have found benefit from VNS in the cessation of seizures in patients with refractory status epilepticus and NORSE. There is limited evidence of its use in FIRES.
Long term effects
The prognosis of FIRES is poor. The outcome varies with the length of the acute phase with mortality rates up to 30%. Of those patients who survive there is 66-100% chance that they will have long term cognitive impairment due to damage of the frontal and temporal lobe functions. Survivors with a normal cognitive function will present with a spectrum of learning disabilities, behavioural disorders, memory issues and sensory changes. There is a high risk of recurrent status epilepticus. Unfortunately, only a small proportion of survivors will have no neurologic sequelae.
The patient required a lengthy PICU admission where they were managed with a burst suppression coma, ketogenic diet, high dose steroids and intravenous immunoglobulin.
They were later diagnosed with Febrile-Infection Related Epilepsy Syndrome after extensive investigations, including a normal brain MRI and a lumbar puncture which showed a mildly elevated white cell count but was otherwise unremarkable.
They are currently seizure free on a combination of oral phenobarbitone, perampanel and levetiracetam but have some cognitive sequelae.
References