Meet Jasmine, a 23-month-old girl with a background of recurrent viral-induced wheeze. Today, she’s come in with a three-day history of coryzal symptoms and has been struggling with her breathing since this morning. Her mum had been giving 10 puffs of salbutamol at home but it didn’t seem to be making much difference so she’s brought her into your Paediatric ED.

On examination, Jasmine looks pale. There’s a scattered wheeze and a few basal crepitations. She has moderate abdominal breathing with some associated tracheal tug.

Her observations are up:

Ouch, you don’t like the look of those oxygen saturations. She’s not that wheezy, but you wonder if she will open up with a bronchodilator and is currently too tight for you to hear much wheeze.  

You pop on high flow oxygen at 15 L/min but what do you prescribe?

As you are about to pick up the next card, some of the medical students you’ve worked with before ask if they can follow the case with you. “We’ve barely seen any wheezy kids in our whole placement,” they say. “Of course,” you reply, “but we’ve barely seen any during the pandemic either… I might need your help remembering how to treat her!”

You recap the case for them and explain what treatment you have decided to give first.

“Wouldn’t you ever use nebulised magnesium in a case like this?” one of the students asks. “I am sure I read that the BTS/Sign guideline suggests it for all children with sats of less than 92% at presentation?”

You pull the guideline up on your phone.

They’re right. However, you’ve never done this in practice. As far as you remember the evidence around nebulised magnesium is mixed.

In 2013 the Lancet published the results of the MAGNETIC trial.

This, you explain, was an RCT designed to compare standard acute asthma treatment with standard treatment plus nebulised magnesium sulphate. 500 children aged 2-16 years with acute severe asthma were randomised to receive either nebulised magnesium sulphate in addition to salbutamol or placebo plus salbutamol. They found no difference in the asthma severity score at 60 minutes post randomisation. However, they did note, that magnesium made more difference to those with more severe symptoms at presentation and a short duration of wheeze.

Following this there was some enthusiasm for giving magnesium to children with short duration of severe wheeze, but, you continue, it’s never really caught on. Last year, a large study of over 800 2 to 17 year olds with acute wheeze, showed absolutely no benefit of magnesium sulphate over placebo: there was no difference in hospitalisation within 24 hours or change in asthma severity score at four hours. “So, in answer to your question,” you tell the students, “it’s probably not going to make much difference here.”  

As you finish explaining, Jasmine’s nurse comes in to find you. ”Can you come and review Jasmine please?” she asks. “She’s not looking too great.”

And she’s right, in fact Jasmine barely looks any better than when she arrived. She is more tachycardic and feels cool at her hands and feet. She is still recessing, a bit less wheezy, and the oxygen saturations, in 15L, are sitting at 96%.

Hmmm… you think to yourself… she needs another neb and if she doesn’t improve after that we’ll have to escalate things…

While Jasmine’s nurse gets the next nebuliser ready, you wonder whether a dose of steroids wouldn’t go amiss. At almost two years old, with a history of similar episodes, this sounds like a case of viral induced wheeze to you.

You know from Foster’s 2018 trial, that in children with pre-school wheeze, steroids made no difference to acute change in respiratory score or time to ED discharge. The key benefit they showed was reduction of length of hospital stay amongst children who were admitted.

This could be Jasmine. But you’re not sure which way she’s going yet… So what do you prescribe?

It’s time for a clinical review. But Jasmine looks worse. She is still tachycardic, a bit mottled, wheeze is unchanged and she’s more tachypnoeic.

“She’s not responding,” you say. “We’re going to need an IV bronchodilator after all.”

You insert a line for IV treatment and take a gas and a few other bloods while you are at it. You decide to make your consultant aware that Jasmine is looking pretty sick. They agree she needs an IV bronchodilator and will pop down to review straight away.

You sit down to prescribe her treatment…

But what drug are you going to give?

Finally, the infusion is up and running. You decide now is a good moment to grab a round of coffees for the team. But, to your horror, whilst standing in the queue, the crash buzzer goes off… you sprint back to the department wondering who on earth it can be for…

…and arrive to find Jasmine having CPR.

Jasmine turned pale after the infusion started, became more tachycardic, then hypotensive and then crashed.

The play specialist is crying as she thinks she overstimulated her with the bubbles. “It’s not that,” you reassure her, “I think we must have missed something here.”

But despite a sterling resuscitation and the team’s best efforts, Jasmine does not survive. Fortunately for you, this is not real life, it’s a PEM adventure and so we get to go back in time…..

And THIS time, you’re handed the gas before you write up the IV bronchodilator.

“Oh rats,” you think. Tachycardia, hypotension, raised lactate. This must be sepsis. Hastily you prescribe 80mg/kg ceftriaxone and a 20ml/kg saline bolus.

But to your dismay this just puts Jasmine’s heart rate up even further.

At that moment your consultant arrives.

“Hmm… calcium’s a bit low,” they say.

Your mind is racing… why is the calcium low? Her lactate, her tachycardia, her poor response to bronchodilators and fluid is all starting to feel decidedly cardiac to you.

Jasmine starts to look drowsy and a worrying shade of pale. You order a portable CXR and your consultant suggests a dose of calcium gluconate – just in case. As all this is being organised, you recap the story so far.

“This is 23 month-old Jasmine. She presented with three days of coryzal illness followed by difficulty in breathing and wheeze. She’s had an oxygen requirement since she got here and was working hard with mild wheeze on auscultation. We gave salbutamol nebulisers plus ipratropium and a dose of steroids with little effect on her tachypnoea. She’s been here for about an hour and a half and has become more tachycardic, with a poor gas. We were about to give an IV bronchodilator,” you explain, “but with that gas I am really concerned we are missing something.”

Together you and your consultant re-examine Jasmine. She’s pale, peripherally mottled and tachycardic. Her BP is holding at 75 systolic. Her heart sounds are so fast you can’t tell if there’s a murmur or not. Her peripheral pulses are thready and those basal creps are now worse. Her liver is palpable 5cm below the costal margin

“Its got to be cardiac,” you conclude. “Shall we get her round to resus?”

Round in resus you pull up Jasmine’s x-ray. Her lungs look a little wet to you.

And it all starts to make sense. No wonder she didn’t get better with salbutamol – it never was bronchial asthma in the first place. It must have been cardiac wheeze secondary to rapid onset pulmonary oedema. “This must be a cardiomyopathy or myocarditis,” you say out loud. You know you know you need to support Jasmine’s sick myocardium with a vasoactive agent and fast.

But which one are you going to choose?

You call the local cardiac centre who agree, Jasmine should be treated as having cardiogenic shock and suggest that starting a peripheral or IO adrenaline infusion at 0.01mcg/kg/min is the safest first line option.

“What about milrinone?” you ask. They explain that they would prefer to wait until Jasmine’s BP is more stable as milrinone can vasodilate before it starts to work as an inotrope. It’s best given, they advise, once she’s safely arrived at their end and had an echo to confirm the diagnosis.

They would like you to intubate to reduce myocardial demand once the adrenaline infusion is up and request immediate transfer to their unit – no more fluid boluses. In fact, they suggest, have adrenaline boluses ready for intubation: draw up the arrest dose into a 10 ml syringe and dilute with saline so it can be given in 1ml aliquots at a tenth of the arrest dose to support the BP if needed.

If possible put in an arterial line, or at the very least cycle the BP every minute. Oh and of course, don’t forget an ECG.

Jasmine is successfully intubated for transfer using ketamine, rocuronium and fentanyl in a 1:1:1 ratio.

As you finally sit down to write some notes, the medical students from earlier approach.

“This has been fascinating,” they say. “We’d like to present this case at grand rounds. Myocarditis: the master of disguise. And we found this great paper…”

Freedman et al. Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation. Pediatrics 120; 6:1278-85 December 2007 

Freedman and colleagues performed a retrospective review of paediatric patients who attended the Hospital for Sick Children in Toronto with myocarditis between May 2000 and May 2006. There were 16 cases of definite (biopsy-proven) myocarditis and 15 cases of probable myocarditis. And when looked at the demographics of the sample they found a few interesting things:

• Age was not normally distributed, with peaks among children under three years and over 16 years of age
• In their cohort:
  • 32% presented with predominantly respiratory symptoms
  • 29% had cardiac symptoms
  • 6% had gastrointestinal symptoms  
  • But this was significantly associated with age…
• Half of under 10’s had primarily respiratory symptoms
• None of the under ten’s had cardiac symptoms or chest pain at presentation
• The two children with gastroenteritis symptoms were also under ten.
• Initial misdiagnosis with pneumonia or asthma happened in 57% of cases.
• 25% of children were admitted with a different diagnosis to begin with.

This starts to make you feel a little better.

“But it’s not only symptoms that can be misleading,” the students continue. The paper looked at the relevance of investigations too:

• Just over (55%) half of initial chest x-rays were abnormal.
• Typical signs when present included cardiomegaly, pulmonary venous congestion and pleural effusion.
• ECG was more sensitive with 93% abnormal at presentation

Signs included: ST or T wave abnormalities, axis deviation, ventricular hypertrophy, infarction pattern, decreased voltage, atrial enlargement and AV block.

• Aside from troponin (which wasn’t assessed as it was measured at presentation in less than 30% patients), AST was the most useful biomarker for potential myocarditis and a value over 100 U/L was significantly associated with cardiac disease

Well, you think to yourself as Jasmine leaves the building with the retrieval team, sick but more stable, every day’s a school day. As you reflect on the biases influencing your decision making through Jasmine’s ED journey, you remind yourself to keep a more open mind in the future. And you save the date in your diary for the medical student’s grand round presentation.

Jasmine makes a complete recovery and one year later comes to visit you in PED. She and her Mum have been busy fundraising and she is here, full of 3 year old attitude, ready to donate the proceeds to your department.

But before we go, lets hop back in that PEM adventures time machine one more time and see what was the learning from Jasmine’s case.

Nebulised MgSO4

The MAGNETIC trial in 2013 was an RCT designed to compare standard acute asthma treatment with standard treatment plus nebulised magnesium sulphate (2).

Powell, C., Kolamunnage-Dona, R., Lowe, J., Boland, A., Petrou, S., Doull, I., Hood, K., Williamson, P. and MAGNETIC Study Group, 2013. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. The Lancet Respiratory Medicine, 1(4), pp.301-308.

They randomised 500 children aged 2-16 years with acute severe asthma to receive either nebulised magnesium in addition to salbutamol or salbutamol plus placebo. They found no difference in the asthma severity score at 60 minutes post randomisation. However, they did note that magnesium made more difference to those with more severe symptoms at presentation and a short duration of wheeze.

Last year, a large multicentre Canadian study of over 800 2-17-year-olds with acute wheeze (3) showed absolutely no benefit of magnesium sulphate over placebo. They randomised children with persistent signs of moderate to severe wheeze after initial treatment with three albuterol and ipratropium nebulisers and steroids to receive either magnesium sulphate or placebo to be administered alongside three further albuterol nebulisers.  The primary outcome measure for this study was hospitalisation within 24 hours. They found no difference between groups in hospitalisation or change in asthma severity score at 4h post-treatment.

So, although the BTS guideline still does recommend this, in practice its not used widely in UK emergency departments and although it’s unlikely to do harm, it probably won’t make a huge difference to the patient in front of you.

Steroids for preschool wheeze

Two well-known studies on this topic are those by Foster in 2018 (4) and Panickar in 2009 (10) and for a great discussion on these have a read of this DFTB blog (11)

Panickar, J., Lakhanpaul, M., Lambert, P.C., Kenia, P., Stephenson, T., Smyth, A. and Grigg, J., 2009. Oral prednisolone for preschool children with acute virus-induced wheezing. New England Journal of Medicine, 360(4), pp.329-338.

In 2009, Panickar and colleagues performed a double blind RCT in children aged 10-60 months with acute virus induced wheezing across three UK centres (10). They randomised 700 children to receive a 5-day course of either prednisolone or placebo after initial albuterol treatment and measured the PRAM score at 4 hourly intervals from enrolment to hospital discharge.

Their primary outcome measure was duration of hospital stay and the trial found no significant difference between groups on this measure. There was also no difference in PRAM scores at any time interval or readmission within 1 month. And this held even when performing a subgroup analysis of children at higher risk of an atopic asthma phenotype. Of course, the caveat to this study, is the age range included in the trial. Infants in the ten months to 2 years age group show a degree of heterogeneity in disease phenotype; many will have a bronchiolitic illness rather than an inflammatory viral induced wheeze and respond differently to steroid medication (12).

Foster, S.J., Cooper, M.N., Oosterhof, S. and Borland, M.L., 2018. Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. The Lancet Respiratory Medicine, 6(2), pp.97-106.

Foster and colleagues performed a similar trial in 2018 (4) randomising 600 children aged 24-72 months presenting with virus-associated wheezing, to receive prednisolone or placebo. They chose this age range specifically to avoid the confusion of including patients with bronchiolitis in the sample.

They also found that steroids made no difference to acute change in respiratory score or time to ED discharge. However, amongst children who were admitted to hospital, total length of stay in the steroid group was reduced. There was no difference in re-attendance or PICU admission but of note, children with the most severe symptoms or co-morbidities at presentation (for example, oxygen saturations <92% in air; a silent chest; shock or sepsis; previous PICU admission with wheeze; prematurity; other cardiac or respiratory disease) were excluded. So for this group, which would certainly include Jasmine, the question perhaps remains unanswered.

Wallace, A., Sinclair, O., Shepherd, M., Neutze, J., Trenholme, A., Tan, E., Brabyn, C., Bonisch, M., Grey, N., Johnson, D.W. and McNamara, D., 2021. Impact of oral corticosteroids on respiratory outcomes in acute preschool wheeze: a randomised clinical trial. Archives of Disease in Childhood, 106(4), pp.339-344.

A further trial, published last year by Wallace and colleagues (13), randomised 493 children aged 24-59 months to receive either prednisolone or placebo. They found no difference between groups in the primary outcome measure – change in baseline PRAM score at 24 hours and 7 days. However, they noticed with interest, that the median PRAM score at 24 hours was zero in both groups with only a small number of children remaining symptomatic at this time point.  This they argue, illustrates how viral-induced wheezing attacks may often be short-lived in nature and the most important benefits of steroids, if any, must occur within that initial 24-hour period.

Within the first 24 hours, they did find some benefit of prednisolone over placebo: those in the prednisolone group had significantly lower PRAM scores 4 hours after medication administration which translated into a reduced requirement for hospital admission, additional steroid or intravenous treatment. A particular strength of this study was the analysis of several subgroups for salbutamol responsiveness, positive Asthma Predictive Index and baseline severity. The subgroup analysis showed that the primary outcome measure (PRAM score at 24 hours and 7 days) was not modified by any of these factors, however, the analysis was not extended to the secondary outcomes (ie what happened within those first 24 hours).

This is a shame as it is increasingly well recognised that several different wheezing phenotypes exist and that these may determine response to standard asthma therapies. Ultimately, the answers we are looking for may come from studies such as the DOORWAY (Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth) (14) project. This exciting study aims to identify genetic determinants of responsiveness to steroids so that one day clinical management can be better individualised.

Dexamethasone or prednisolone?

This is an interesting question that has been raised within the PEM community in recent years. Early studies show single dose dexamethasone is non inferior to a 3 day course of oral prednisolone for children attending ED with wheeze. It sorts out the respiratory symptoms, is overwhelmingly less likely to get vomited up and doesn’t need to be given by parents for two further days at home.

For example, the original trial by Cronin and colleagues showed no significant difference in day 4 respiratory score or unscheduled reattendance when they compared dex to pred for wheezing children aged 2-16 (5). This finding has been replicated in many subsequent trials as Wei and colleagues summarise in their recent systematic review (6).

Wei and colleagues looked at 7 trials comparing dexamethasone to prednisolone for the treatment of acute wheeze , specially aiming to compare relapse rates and adverse effects. Six out of the seven trials included children from age 2 to adult – avoiding the inclusion of those with potential bronchiolitis, but clearly including a mix of both atopic asthmatics and those with viral induced pre-school wheeze.  

Wei and colleagues found no significant difference between dexamethasone and prednisolone on relapse rate up to five days post treatment or 10-15 days of follow-up and this held whether children received one or two doses of dexamethasone. There was no difference in hospital readmission rates or adverse events between the two drugs, however the incidence of vomiting both in hospital and at home was significantly higher in the prednisolone group.

Sounds like a no-brainer then? Unfortunately, not quite. Conscious of the relatively small number of quality trials conducted on this topic, Wei and colleagues conducted a power calculation to determine the validity of their results. This showed the meta-analysis was underpowered to accurately answer the questions posed. Whilst their results are suggestive that dexamethasone is at least equivalent to prednisolone, they caution that further and larger studies on the topic are required before strong conclusions can be drawn.  In addition, further studies should try to differentiate dexamethasone response between pre-school wheezers and those with a more atopic phenotype as anecdotal evidence suggest there is likely to be a difference between these two groups.

Again, this is all going to come back to findings of projects such as DOORWAY which should one day help us to provide more nuanced care.

IV bronchodilators

Despite the fact that an acute exacerbation of wheeze or asthma represents the bread and butter of acute paediatrics, we have a yet to achieve consensus for the best way in which to treat it.  It is widely accepted that inhaled bronchodilators and steroids are the best first-line approach, but there are several options for second line IV treatment (IV beta-agonists, IV adrenaline, IV magnesium sulphate, IV methylxanthines and IV ketamine) and no evidence with which to separate them. A few years ago PERUKI conducted a survey to establish prescribing practices for second line asthma treatments amongst senior UK based ED clinicians (15) and this clearly illustrated wide variation in practice around the UK. Magnesium sulphate was the most frequently prescribed first IV infusion but this was by no means universal.

Last year a Cochrane review of systematic reviews on treatments for asthma (7) was conducted, the aim being to try and unravel the story here a little better. They included 13 Cochrane Systematic Reviews on various treatment options for acute asthma. Primary outcomes were length of stay, hospital admission, intensive care unit admission, and adverse effects. Four of the 13 reviews focussed on IV medication although none compared all three big players (beta agonists, magnesium sulphate and methylxanthines) head-to-head. No single agent was identified as being able to reduce risk of ITU admission. And no one single agent appeared markedly superior to the others for any of the primary outcome measures.

What we need, is a well-designed and adequately powered, large scale RCT to directly compare the three most commonly used IV bronchodilator treatments, including subgroup analyses in preschool and school‐aged children, and for varying degrees of asthma severity.

Myocarditis

This case was a great illustration of the difficulties that can arise in the early identification of acquired cardiac pathology, particularly in younger children who do not tend to complain of cardiac symptoms and may present with a predominantly respiratory or non-specific picture. The key to diagnosis is recognising when there is a lack of expected response to treatment and picking up on the small signs that can give the game away. The astute amongst you may have noticed Jasmine’s unusually wide pulse pressure at presentation. Perhaps, if you had been the doctor examining, you’d have felt for the liver a little earlier on too?

From a PED management perspective the key to success is firstly in recognising the problem and getting early expert advice.

Myocarditis has been defined as an “inflammatory disease of the heart muscle” and has a variable clinical presentation, with several distinct disease phenotypes (16). As in Jasmine’s case, it is commonly viral in origin (think enterovirus/coxsackie/adenovirus and parvovirus). But there are some other important differentials to consider as well:

• Familial Cardiomyopathy/metabolic
• Cardiac Structural abnormality (ALCAPA/Coarctation)
• Idiopathic dilated cardiomyopathy
• Hypocalcaemia and Vitamin D deficiency (8)

Classic myocarditis may have a relatively insidious onset with worsening fatigue and exertional dyspnoea or in older teenagers may mimic an acute coronary syndrome. It is associated with echocardiographic findings of left ventricular dilatation (which may be indistinct from a dilated cardiomyopathy picture), reduced ejection fraction, segmental wall abnormalities +/- pericardial effusion (16).

Fulminant myocarditis is a distinct symptom complex, and when supportive care is administered in a timely fashion, typically enjoys a higher rate of complete recovery of function. It may present with a history of recent viral illness followed by sudden-onset heart failure usually within 2-4 weeks and usually has more severe ventricular dysfunction. In contrast to classic myocarditis, it has an echocardiographic phenotype of reduced left ventricular ejection, normal left ventricular cavity size, and increased septal thickening.

Fulminant myocarditis conversely is a distinct symptom complex. It typically follows a viral illness and presents with sudden onset heart failure as in our case above. Echocardiographic findings typically show reduced left ventricular ejection, normal left ventricular size and increased septal thickening. Heart size on chest x-ray may not be hugely increased (16). Provided appropriate supportive measures are initiated early, long-term prognosis is often better in this group (16).

Management – both in ED and PICU – is predominantly supportive.

Inotropes are the best way to support the child, like Jasmine, presenting in cardiogenic shock. And heart failure should be managed according to published guidelines once the child is stabilised (17). Adrenaline is recommended as a first line infusion where there is evidence of hypotension and poor end organ perfusion. Milrinone and/or dobutamine are of benefit once BP has stabilised (17). The child should be intubated and ventilated but make sure you’ve gone through your intubation checklist and be prepared for a bumpy ride as these patients are notoriously unstable and will arrest with even slight changes to their compensatory physiology.

Despite much debate and equivocal evidence of benefit (18), in PICU Jasmine received a dose of IVIG and over the course of 10 days was gradually weaned off milrinone.  She made an excellent recovery with a return to normal ventricular function 6 months later. Unfortunately, many children are not as lucky and will require ECMO – either as rescue therapy or as a bridge to transplant.

Jasmine was 23 months old, but for children under 10kg ECMO as a bridge is problematic, both ethically and clinically: there’s a small pool of eligible hearts and ECMO is a finite resource.  The answer may be a left ventricular assist device, where there have been growing reports of success, including amongst the very young (19) … but that’s for another PEM adventure.

References

1. SIGN158 British guideline on the management of asthma: A national clinical guideline. First published 2003 Revised edition published July 2019
2. Powell et al. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised controlled trial.  The Lancet Volume 1; 4: 301-308 June 2013
3. Scuh at al. Effect of nebulized magnesium vs placebo added to albuterol on hospitalization among children with refractory acute asthma treated in the emergency department: a randomized controlled trial. JAMA. 2020;324(20):2038-2047.
4. Foster et al.  Oral prednisolone in pre-school children with virus-associated pre-school wheeze: a prospective, double blind, randomised controlled trial. The Lancet. Volume 6, Issue 2. P97-106. February 2018.
5. Cronin et al.  A randomized controlled trial of single dose oral dexamethasone versus multi-dose oral prednisolone for acute exacerbations of asthma in children who attend the emergency department.  Annals of Emergency Medicine: 67;5: 503-601 2016
6. Wei at al. Oral Dexamethasone vs. Oral Prednisone for Children With Acute Asthma Exacerbations: A Systematic Review and Meta-Analysis. Frontiers in Pediatrics. 2019 Dec 13;7:503. doi: 10.3389/fped.2019.00503.
7. Craig et al. Interventions for escalation of therapy for acute exacerbations of asthma in children: an overview of Cochrane Reviews. Cochrane Database Systematic Reviews. 2020 August 5;8:CD012977. doi: 10.1002/14651858.CD012977.pub2. PMID: 32767571.
8. Maiya et al. Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure. Heart 94.5 (2008): 581-584.
9. Freedman et al. Pediatric myocarditis: emergency department clinical findings and diagnostic evaluation. PEDIATRICS 120; 6:1278-85 December 2007 
10. Panickar et al. Oral prednisolone for preschool children with acute virus-induced wheezing. New England Journal of Medicine. 2009 Jan 22;360(4):329-38. doi: 10.1056/NEJMoa0804897. 
11. Tessa Davis. Steroids for pre-school wheeze, Don’t Forget the Bubbles, 2018. Available at:
    https://doi.org/10.31440/DFTB.14563
12. Fernandes RM et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD004878. DOI: 10.1002/14651858.CD004878.pub4).
13. Wallace et al. Impact of oral corticosteroids on respiratory outcomes in acute preschool wheeze: a randomised clinical trial. Archives of Disease in Childhood2021;106:339-344.
14. Tse SM et al. DOORWAY research group of the Pediatric Emergency Research in Canada (PERC) network. Genetic determinants of acute asthma therapy response in children with moderate-to-severe asthma exacerbations. Pediatric Pulmonology. 2019 Apr;54(4):378-385. doi: 10.1002/ppul.24247. Epub 2019 Jan 15.
15. Morris et al. Which intravenous bronchodilators are being administered to children presenting with acute severe wheeze in the UK and Ireland? Thorax. 70(1):88-91. January 2015.
16. Dasgupta et al. Myocarditis in the paediatric population: a review. Congenital Heart Disease. 2019;14:868–877.
17. Kirk et al. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary. The Journal of Heart and Lung Transplantation, Vol 33, No 9, September 2014
18. Robinson et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. 2020 Aug 19;8:CD004370. doi: 10.1002/14651858.CD004370.pub4. PMID: 32835416.
19. Ghelani et al. Demographics, trends and outcomes in pediatric acute myocarditis in the United States 2006 to 2011. Circulation: Cardiovascular Quality and Outcomes. 2012; 5:622-627.