Nebulised magnesium sulphate for asthma?

Cite this article as:
Abdul Safras. Nebulised magnesium sulphate for asthma?, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.31503

Acute asthma is a common presentation to the Paediatric Emergency Department. Treatment is adjusted depending on the child’s clinical acuity, but commonly includes inhaled salbutamol (a beta-2 agonist), oral corticosteroids, and – in more severe cases – inhaled ipratropium (an anticholinergic). However, some patients with moderate to severe asthma do not respond to this treatment.

 Magnesium sulphate is commonly used intravenously as an escalation of care, with evidence supporting reduced hospital admission in children. The 2019 NICE-accredited BTS / SIGN guideline on the management of asthma suggests magnesium sulphate can be nebulised with salbutamol and ipratropium in children with a short duration or acute severe asthma with oxygen saturations below 92%. But how effective is nebulised magnesium sulphate?

Schuh S, Sweeney J, Rumantir M, et 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 Clinical Trial. JAMA. 2020;324(20):2038–2047. doi:10.1001/jama.2020.19839

Clinical question

What is the effectiveness of nebulized magnesium added to inhaled short-acting beta-agonists in children and adolescents with acute asthma in the emergency department who remain in moderate or severe respiratory distress after evidence-based standardized initial therapy?

Design and setting

A randomized double-blind parallel-group clinical trial conducted over 8 years from September 2011 to November 2019, in 7 tertiary-care paediatric emergency departments in Canada. Randomization allocations were concealed to maintain blinding.

PICO image

Population

Children 2 to 17 years of age were eligible if they had a diagnosis of asthma made by a physician, had a previous episode of acute wheeze, and had persistent moderate to severe asthma after completing 1 hour of initial treatment. This treatment included systemic steroids, three doses of inhaled ipratropium bromide and three doses of inhaled salbutamol.

Intervention

Three consecutive nebulisers, consisting of 5 mg of salbutamol (known as albuterol in Canada) and 600 mg (1.2 mL) of magnesium sulphate.

Control

Three consecutive nebulisers containing 5mg of salbutamol, but instead of magnesium sulphate, the nebulisers contained 1.2 mL of 5.5% saline placebo.

The magnesium and placebo solutions were identical in volume, colour, taste, and smell, both in the steady state and during nebulization. Study participants, research nurses, ED staff, and the study analyst were blinded to the treatment assignment.

Outcome

The primary outcome was whether the treating physician decided to hospitalise children in the study due to persistent respiratory distress or the need for supplemental oxygen within 24 hours of randomisation.

The secondary outcomes included adverse effects, changes in PRAM score, respiratory rate, oxygen saturations or blood pressure, hospitalisation or revisits within 72 hours or administration of IV magnesium after the experimental therapy.

Exclusions

Several exclusion criteria were applied. Children requiring immediate airway management; children who received IV magnesium prior to enrolment; children with comorbidities such as chronic lung disease, cardiovascular, kidney, neurologic, or other systemic disease; and children with a known hypersensitivity to magnesium. Families without adequate command of the English or French language, without telephone or e-mail contact information, and those previously enrolled were also excluded.

What is the PRAM score?

PRAM (Paediatric Respiratory Assessment Measure) is a 12-point clinical scoring system that captures a patient’s asthma severity using a combination of scalene muscle contraction, suprasternal retractions, wheezing, air entry and oxygen saturation. PRAM was originally developed for patients aged 3 – 6 years and subsequently validated in children aged 1 to 17 years old.

Asthma scores are commonly used in the USA and Canada, however, are much less frequently used in the UK, Ireland, Australia and NZ. A recent PERUKI survey found that none of 59 hospitals routinely collected enough information to be able to calculate a PRAM score for asthma patients.

That being said, a PRAM score of 4-7 is considered “moderate” asthma, while 8 or more suggests “severe” illness.

Analysis

Of a total of 5846 screened patients, 4332 met various exclusion criteria (the most common was the 2740 patients who had a PRAM score of 4 or less after initial therapy), 273 declined participation, and another 423 did not participate, mostly due to absence of a primary caretaker.

818 children were randomised and the results of 816 children were analysed (two children were excluded, one from each group, because they were lost to follow or not eligible).

What did they find?

The primary outcome was hospital admission within 24 hours. 178 of the 409 children in the magnesium sulphate group (43.5%) were hospitalised, compared to 194 of the 407 children in the placebo group (47.7%). The difference between groups was 4.2%, however, the 95% confidence intervals range from -11% to 2.8%, suggesting that there may be no significant difference.

The were no differences in any secondary outcomes between the two groups: no difference in change in PRAM score from baseline at 240 minutes (4 hours); no difference in hospitalisations; no difference in revisits within 72 hours; and no difference in administration of IV magnesium after the experimental therapy.

There were relatively more adverse events in the magnesium group than the placebo group, but more serious adverse events in the placebo group. All observed serious adverse events consisted of admissions to PICU and none were attributed to the experimental therapy.

There was no difference in outcome between “intention to treat” analysis (all patients enrolled in the study) and “per protocol” analysis (those who completed all three assigned treatments), and no difference demonstrated for those with more severe asthma.

Clinical bottom line

Children with acute asthma who received nebulised magnesium with salbutamol did not have a significantly lower hospitalisation rate than those given salbutamol alone. This study suggests that patients who present with moderate to severe asthma will not benefit from nebulized magnesium sulphate added to salbutamol.

Will it change my practice? – Simon Craig

This is a well-conducted study from the Pediatric Emergency Research Canada (PERC) network and highlights how challenging it is to conduct high-quality research. The authors made an incredible effort to recruit over 800 patients from 7 hospitals over an 8-year period.

Although magnesium alone has some bronchodilator properties (when compared to placebo), it doesn’t look like it’s worth adding to inhaled salbutamol for children who are still unwell after initial asthma therapy.

This study also makes me wonder how good IV magnesium really is… It will be very interesting to see the various paediatric emergency research networks try to tackle large multicentre trials to answer some of the big “IV therapy for asthma” questions. Australian, UK and Irish guidelines don’t recommend inhaled magnesium, and I doubt they will change as a result of this study.

ng key info for the paper

References

Chalut, D.S., Ducharme, F.M., & Davis, G.M. (2000). The preschool respiratory assessment measure (PRAM): A responsive index of acute asthma severity. Journal of Pediatrics, 137(6), 762-768.

Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, Meng L, McGillivray D. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr. 2008 Apr;152(4):476-80, 480.e1. doi: 10.1016/j.jpeds.2007.08.034. Epub 2007 Oct 31. PMID: 18346499.

Cheuk DK, Chau TC, Lee SL. Ameta-analysis on intravenous magnesium sulphate for treating acute asthma. Arch Dis Child. 2005;90(1):74-77. doi:10. 1136/adc.2004.050005

Liu X, Yu T, Rower JE, Campbell SC, Sherwin CM, Johnson MD. Optimizing the use of intravenous magnesium sulfate for acute asthma treatment in children. Pediatr Pulmonol. 2016;51(12):1414-1421. doi:10.1002/ppul.23482

https://www.chusj.org/CORPO/files/32/32ba0b8c-4894-4d8e-87ca-a46e4c0924a5.pdf

https://www.asthmahandbook.org.au/acute-asthma/clinical/add-on-treatment

It’s Only Wheeze – Treatment Is Simple, Isn’t It?: Meredith Borland at DFTB19

Cite this article as:
Team DFTB. It’s Only Wheeze – Treatment Is Simple, Isn’t It?: Meredith Borland at DFTB19, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.20828

Meredith Borland is a paediatric emergency physician and the Director of Emergency Medicine at Perth Children’s Hospital in Perth, Western Australia. She was a founding member of the PREDICT Executive and is the current chair of PREDICT.

Last year at DFTB18, Meredith continued an ongoing discussion about the use of steroids in wheeze. This year, she took us on a journey through an emergency department visit for a number of children who may or may not receive various interventions. This was a fun, interactive and thought-provoking talk that highlighted some common differences in practice.

#doodlemed on this talk by @char_durand below

This talk was recorded live at DFTB19 in London, England. With the theme of  “The Journey” we wanted to consider the journeys our patients and their families go on, both metaphorical and literal.

If you want our podcasts delivered straight to your listening device then subscribe to our iTunes feed or check out the RSS feed. If you are more a fan of the visual medium then subscribe to our YouTube channel. Please embrace the spirit of FOAMed and spread the word.

The 39th Bubble Wrap

Cite this article as:
Leo, G. The 39th Bubble Wrap, Don't Forget the Bubbles, 2020. Available at:
https://dontforgetthebubbles.com/the-39th-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 the UK and Ireland) to point out something that has caught their eye.

Asthma Module

Cite this article as:
Miriam Saey Al-Rifai. Asthma Module, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.27232
TopicAsthma
AuthorMiriam Saey Al-Rifai
DurationUp to 2 hours
Equipment requiredNone
  • Basics (10 mins)
  • Main session: (2 x 15 minute) case discussions covering the key points and evidence
  • Advanced session: (2 x 20 minutes) case discussions covering grey areas, diagnostic dilemmas; advanced management and escalation
  • Sim scenario (30-60 mins)
  • Quiz (10 mins)
  • Infographic sharing (5 mins): 5 take home learning points

We also recommend printing/sharing a copy of your local guideline.

Joseph, a 10 year old boy comes into the ED. He is a known asthmatic on treatment. He appears breathless with an audible wheeze. He is able to talk in complete sentences. He has a RR of 25, sats of 94%, pulse of 100 and his PEF is 60% of normal.

What is the severity score of this child’s asthma presentation?

What investigations and treatment options should you consider?

How do you decide when it is safe to discharge home?

The boy is 3 years old with the same presentation – his mum asks you if her son has asthma. What is your response?

When seeing a child with an acute asthma attack, the initial assessment is key to establishing the severity of the attack as this influences ongoing management. 

The following clinical signs should be recorded:

Pulse rate – Increasing tachycardia generally denotes worsening asthma; severe airway obstruction can result in pulsus paradoxus and a fall in heart rate in life-threatening asthma is a preterminal event.

Respiratory rate and degree of breathlessness –  Ie too breathless to complete sentences in one breath or to feed.

Use of accessory muscles of respiration – subcostal, intercostal recessions, tracheal tug. You can also assess by palpation of neck muscles. Also consider including a prolonged expiratory phase.

Amount of wheezing – which might become biphasic or less apparent with increasing  airways obstruction. Silent chest is an indicator of life threatening asthma. It is important to auscultate and document any improvement with treatment.

Degree of agitation and conscious level – always give calm reassurance.

Observations

  • Include general observations.

CXR

  • NOT routinely advised. A chest X-ray should be performed if there are persisting unilateral signs suggesting pneumothorax, inhaled foreign body, lobar collapse or consolidation and/or life-threatening asthma not responding to treatment.

Blood Gas

  • Only indicated if not responding to treatment or needing further escalation of care

Oxygen 

  • If any life threatening features or sats <94%. Aim for sats 94-98%

Inhaled β2 agonist 

  • Salbutamol up to 10 puffs via spacer (1 puff = 5 breaths) assess after 15 mins and repeat if necessary. If sats <94% use,or patient refusal/poor inhaler technique use salbutamol nebulisers (2.5 – 5mg).
  • Continuous nebulisation may be better, as intermittent may result in rebound bronchoconstriction. 

Ipratropium Bromide 

  • If symptoms are refractory to initial β2 agonist treatment, add ipratropium bromide (250 micrograms/dose mixed with the nebulised β2 agonist solution) every 20-30 mins for the first two hours in severe asthma attacks. This should then be tapered to 4-6hrly before being discontinued. However, there are no clinical trials supporting ipratropium use beyond the first hour or first 3 doses in children (EMCases).
  • In a systematic review and meta-analysis comparing the use of beta-agonists plus anticholinergics with beta-agonists alone, combination therapy was associated with significantly lower hospitalisation rates and improvements in asthma scores and pulmonary function test results (EMCases).

Oral steroids 

  • Give oral steroids in the management of acute asthma attacks. Dexamethasone is starting to be used more, as a once only dose, but there is no evidence for benefit over Prednisolone, so not recommended yet. 

Nebulised Magnesium 

  • Nebulised magnesium sulphate is not recommended for children with mild to moderate asthma attacks. The RCT entitled MAGNETIC trial in 2013 of about 500 children showed that MgSO4 nebulisers added to the salbutamol and ipratropium bromide nebuliser in the first hour, for kids with acute severe asthma, significantly improved asthma severity scores without any increase in adverse events.

Antibiotics 

  • Insufficient evidence to refute or recommend.

Burst therapy – improves forced expiratory volume with an earlier peak response, and prevents deterioration between doses. Salbutamol 100 mcgs x 10 puffs via inhaler & spacer every 20 mins for 1 hour. Add ipratropium bromide 20 mcgs (x 4 puffs < 5 years, x 8 puffs > 5 years) together with salbutamol as above for severe cases.

BTS/SIGN – Children can be discharged home once requiring no more than 3-4 hourly inhalers (based on a randomised controlled study in 1999), PEF >75% and sats >94% . 

Safe follow up

  • Reducing regime of salbutamol inhaler therapy with a clear plan as to when to come back to hospital (ie. requiring >10 puffs in 4 hours)
  • Ensure good inhaler technique/correct fitting spacer mask. Advise to use the B-agonist BEFORE the inhaled steroid and to wash the mouth out after the steroid inhaler to prevent thrush.
  • If the parent/carer of the child smokes, advise them to stop.
  • Address potentially preventable contributors to the exacerbation, such as exposure to trigger factors
  • Ensure the patient is discharged home with 3-5 days oral steroids. Some trusts are now given single dose Dexamethasone, although prednisolone is still in the national guideline (https://www.stemlynsblog.org/dexamethasone-asthma-children/). 
  • Primary care follow-up in 24-48hrs
  • If second attack in 12 months refer to a secondary care asthma clinic.

Wheeze is a common presentation in the ED and its diagnoses and management differs depending on the age of the child and the detail in the history (Snelson et al, 2019). 

An age based approach to wheeze in children

Bronchiolitis

  • Slow onset of symptoms. 3-4 day period of worsening cough, poor feeding, wheeze and respiratory distress due to inflammation of the airways.

Viral Wheeze

  • Rapid onset of wheeze and respiratory distress over hours due to bronchospasm.

Asthma

  • Described above. 

The age based approach to wheeze can be explained by the changes in a child’s immune system:

  • At birth and in the first few months, immunity is largely provided by maternal antibodies. These antibodies offer protection from most simple viral infections. Acute atopic IgE mediated reactions are very rare. If infections do occur it is likely to be serious bacterial infections. In addition the baby’s own immune system is not yet fully turned on and the response to infection is therefore muted, making the recognition of sepsis difficult in this age group.
  • Preschool age children no longer rely on maternal antibodies. However, their own immune system is still not fully developed. They compensate for this by having heightened and indiscriminate responses to infections. They produce lots of white blood cells, but do not yet have circulating antibodies. You are more likely to see associated problems of viral infections in this age group like transient synovitis. Atopy is becoming more common now. Sepsis is also difficult to recognize in this age group due to the extreme reaction to often uncomplicated viral infections. These children present with viral wheeze. It is worth knowing that there are wheezy presentations in this age group that can look a lot like viral wheeze.  These include bronchomalacia, acute allergy, and cardiac failure due to e.g. acute myocarditis.
  • Older children have a more mature immune system and response to infection is like that of an adult. As the response to infection is less vigorous and indiscriminate than the pre-schoolers, some specific infections like Varicella can cause severe reactions in these children. These children are more likely to have asthma. True asthma is rarely seen under the age of 5 as it requires a fully matured immune system to develop.

Management

  • By looking at the history we can direct our inhaled beta agonist treatment to one that matches a story consistent with bronchospasm. This would include children with likely viral wheeze and asthma.  
  • The best evidence for the use of oral steroids for viral wheeze between the ages of 1 and 5 would suggest that the following group are most likely to have a small benefit (https://gppaedstips.blogspot.com/search/label/Asthma):
  • Children with a diagnosis of asthma
  • Children who have required substantial amounts of inhaled beta-agonist prior to presentation
  • Children whose severity and lack of response to treatment with beta-agonists requires admission to hospital
  • Joseph has presented with features of a moderate asthma attack
  • This can be managed with beta 2 agonist therapy and oral steroids
  • Once Joseph does not need beta 2 agonist bronchodilation for more than 4hrs and obs remain stable he can be safely discharged home with safe follow up.
  • The 3 year old presenting with the same symptoms of sudden onset wheeze and breathlessness, likely has a diagnosis of viral wheeze. They would benefit from beta 2 agonist bronchodilation. They are too young to be diagnosed with asthma, but risk factors for developing asthma could be explored in the history.

Leila, a 13 year old female, known asthmatic on treatment, presented to ED breathless and finding it hard to speak in full sentences. Her oxygen saturations are 92%, HR 130 and RR 35

What is the severity score of this child’s asthma presentation?

What investigations and treatment options should you consider?

When do you need to re-assess response to treatment to decide on discharge vs escalation?

  • In this instance, Leila falls into the acute severe asthma presentation. 
  • As her sats <94% oxygen needs to be given via a facemask. 
  • Beta 2 agonist bronchodilator via a nebuliser (preferably oxygen driven) to be given due to sats <94% and she falls into the severe category. 
  • Oral steroids must be given. This can be given as IV Dexamethasone if too unwell/vomiting.
  • Re-assess response to treatment after 15 minutes. 
  • If no improvement after 15 minutes give a further two beta 2 agonist nebulisers and add Ipratropium Bromide nebuliser. 
  • A consideration of nebulised Mg can be given in acute severe asthma.
  • Plan for admission, escalate and refer to paediatrics for consideration of second line treatment.

Do you know how to use a spacer?

Leila has not improved despite the treatment given in ED as outlined in case 2. Her sats are now 89%, she appears cyanosed and has a poor respiratory effort. On auscultation her chest is quiet. What are the next steps that need to be taken?

How would you rate the severity score of this presentation?

What investigations or treatment needs to be considered?

Which IV medications if any should be used? 

Which important differentials need to be considered?

What escalation plans need to be put in place?

Children with continuing severe asthma despite optimal first-line treatments, frequent nebulised β2 agonists and ipratropium bromide plus oral steroids, and those with life-threatening features, need urgent review by a specialist with a view to management in an appropriate high-dependency area or transfer to a paediatric intensive care unit to receive second-line intravenous therapies. It is important to do a blood gas prior to starting bronchodilators to measure the pCO2 and also to monitor side effects of salbutamol (decreasing potassium and lactic acidosis).

PERUKI (Paediatric Emergency Research in the UK and Ireland network) is a research collaborative of paediatric-specific and mixed adult and paediatric emergency departments (EDs). In 2015 PERUKI carried out a study looking at the variation in practise of the use of IV bronchodilators as a second line treatment in the management of acute asthma in children. There was a large discrepancy between what clinicians felt was the appropriate management and what they actually administered. A survey of 183 clinicians in 30 EDs revealed that when escalating to intravenous bronchodilators, 99 (54%) preferred salbutamol first line, 52 (28%) magnesium sulfate (MgSO4) and 27 (15%) aminophylline. 87 (48%) administered intravenous bronchodilators sequentially and 30 (16%) concurrently, with others basing approach on case severity. 146 (80%) continued inhaled therapy after commencing intravenous bronchodilators. 

Of 170 who used intravenous salbutamol, 146 (86%) gave rapid boluses, 21 (12%) a longer loading dose and 164 (97%) an ongoing infusion, each with a range of doses and durations. Of 173 who used intravenous MgSO4, all used a bolus only. What this demonstrates is the considerable variability in practise and opinion. 

So what is the evidence? (Cochrane review)

IV salbutamol 

  • There have not been enough trials to form a robust evaluation of its benefits.

IV MgSO4 

  • Appears to be safe and beneficial in severe asthma

IV aminophylline 

  • Improves lung function within 6hrs. However, there is no apparent reduction in symptoms, number of nebulised treatments or length of hospital stay. We do not know the impact on oxygenation, PICU admissions or need for NIV. 

IV ketamine 

  • There has only been 1 study conducted, which reveals no known benefit in non intubated children. 

In one RCT comparing IV aminophylline, salbutamol and magnesium in 100 children, a bolus of magnesium sulphate was shown to reduce clinical symptoms faster than the other treatments. There were no significant side effects documented in the magnesium sulphate group. A systematic review of four paediatric trials comparing IV salbutamol with IV aminophylline demonstrated equivalence.

In children who respond poorly to first-line treatments, consider the addition of intravenous magnesium sulphate as first-line intravenous treatment (40 mg/kg/day).

Consider early addition of a single bolus dose of intravenous salbutamol (15 micrograms/kg over 10 minutes) in a severe asthma attack where the child has not responded to initial inhaled therapy. It is not clear whether IV bolus vs infusion is more beneficial. Prior to IV salbutamol administration insure blood potassium is checked and on cardiac monitor. If using an IV infusion monitor lactate to check for toxicity. 

Consider aminophylline for children with severe or life-threatening asthma unresponsive to maximal doses of bronchodilators and steroids. Some of the side effects include abdominal pain, anxiety, headache, nausea, palpitations and seizures. Toxicity can occur with aminophylline. This presents as vomiting (which may be severe and intractable), agitation, restlessness, dilated pupils, sinus tachycardia, and hyperglycaemia. More serious effects are haematemesis, convulsions, and supraventricular and ventricular arrhythmias. Severe hypokalaemia may develop rapidly especially in combination with salbutamol.

Ensuring you have appropriately assessed and optimised their condition

Reassess the patient?

  • Consider revisiting history, respiratory examination and consider adjuncts to assessment such as a capillary or venous blood gas.

Have you exhausted medical management?

  • ? adrenaline ? ketamine ?heliox 

What could be missing? 

  • Consider your confidence of whether you have the right diagnosis or if there is a need to assess for a secondary pathology such as pneumonia, foreign body, anatomic airway anomalies, airway compression by masses/lymph nodes, cardiac disease? Some can be excluded with a good history. Do you need to further investigate with bloods, CXR? Do you need to append your management and provide antibiotic coverage? Do you need to assess for a complication from treatment e.g. pneumothorax.

Escalation options

  • Have you sought a senior review/notified the admitting paediatrician?
  • Do you need an ICU consult, NETS consult or retrieval to a tertiary centre?
  • How long are you comfortable to wait to see if there is a response to IV bronchodilation?

Non invasive ventilation 

  • Is there any evidence in acute asthma attack?
  • What settings/mode would you use?

Does this child need to be intubated?

  • How would you determine this?
  • Who should be involved in the conversation? Who should perform the intubation?
  • What sedation would you use?
  • What equipment would you use?
  • What settings would you use?

Alternative treatment options

Adrenaline

Give for severe or life threatening asthma – if the diagnosis is in doubt. 

Asthma and atopy often co-exist – and in these patients death from anaphylaxis is more likely. So if a patient fails to respond to initial therapy, the diagnosis of anaphylaxis needs to be considered. In addition nebulised Adrenaline causes bronchodilation.  

Heliox 

May improve respiratory score, but it probably won’t reduce the risk of admission. Nor should you use it in routine asthma to stave off intubation (PEMBlog). Can be considered in the ICU setting with maximum oxygen therapy has failed. 

Ketamine

Limited number of trials with mixed outcomes on the benefits of Ketamine. However, it is safe at dissociative dosages, and is a reasonable option when all others measures have failed.

NIV

A few case reports and observational studies of the use of BiPAP in pediatric asthma show some promise. The one RCT of only 20 patients does show a benefit in clinical asthma scores, respiratory rate, and supplemental oxygen need. There is no evidence that it prevents the need for intubation (Basnet S et al, 2012).

Critical care input is the next step for children with severe asthma not responding to treatment or with any life threatening features. There are a number of ongoing trials on the use of ketamine, sevofluorane and NIV, but the evidence is currently lacking so they’re not recommended by BTS/SIGN.

A 15 year old male has been brought into resus with features of life threatening asthma. Pre hospital the paramedics gave continuous salbutamol nebulisers, 500mcg Ipratropium nebulisers and 0.5mg IM Adrenaline. The attending medical team in resus administered 2g IV Mg over 20 mins and a bolus of 250mcg IV Salbutamol. The patient then became unresponsive with no respiratory effort.

What are the next steps that need to be taken?

What is the ‘deadly triad’ in asthma?

What are the key ALS modifications in asthma arrest?

In the pre-hospital setting, paramedics usually give IM Adrenaline to cover for the possibility of a diagnosis of anaphylaxis. 

In this case the patient has arrested. As soon as this has been identified, CPR needs to be initiated as per the ALS guidelines.

The cause of cardiac arrest in asthma is a result of the ‘deadly triad’:

Important modifications and considerations in managing cardio respiratory arrest in asthma (RCEMLearning – https://www.rcemlearning.co.uk/foamed/arrest-asthma/):

  1. Intubate Early

Due to the need for high inflation pressures, an endotracheal tube (ETT) is needed. In addition this protects the airway from the increased risk of regurgitation and aspiration.

  1. Ventilate with caution

The European Resuscitation Council recommends 8-10 breaths per minute with the lowest tidal volume required to see the rise and fall of the chest, to avoid dynamic hyperinflation. Tachypnoea must be avoided as this reducses expiratory time, thus increasing the residual volume in the alveoli. This auto PEEP increases intrathoracic pressure which reduces venous return, impeding CPR. 

  1. Manual chest deflation

If the patient has a hyperinflated chest/poor excursions of the chest wall, disconnect the ETT and apply manual pressure to the patient’s chest to expel the trapped air. 

  1. Consider tension pneumothorax

If ETT disconnection does not improve ventilation, consider performing a bilateral thoracostomy.

  1. Rehydrate

Dehydration and reduced intravascular volume compromises effective CPR. It also causes mucus to be thicker which can plug small airways. So ensure you give IV fluids. 

  1. GIVE ADRENALINE! – Utilise its bronchodilator effect. 

In an acute asthma exacerbation in children, monitoring the oxygen sats is important because:

A: Hypoxaemia is an early sign of clinical deterioration 

B: Sats <95% may suggest the need for prolonged bronchodilator therapy

C: Hypoxaemia occurs in the presence of life threatening asthma. Children may have normal sats for some time before critical desaturation occurs.

D: Sats >96% supports the decision to safely discharge home

The correct answer is C.

In an acute asthma attack hypoxic vasoconstriction occurs. This is coupled with decreased blood flow to the under ventilated lung (matching pulmonary perfusion with alveolar ventilation). 

In the hospital setting SaO2<91% may be a helpful predictor of prolonged frequent bronchodilator therapy more than 4 hours and SaO2 of <89% is associated with a need for bronchodilator therapy over 12 hours.

Hypoxaemia and hypocarbia only occur in the presence of life threatening asthma. Children may have normal sats for some time before critical desaturation occurs. Whilst low oxygen saturations mean that a patient is unwell it should be clinically obvious at this point.  Low oxygen saturations may also represent a degree of mucus plugging that may be helped with repositioning.

Hyperoxia can lead to absorption atelectasis as well as intra-pulmonary shunting with subsequent reduction in cardiac output. In addition concerns have been raised that oxygen administration may lead to potential delay in recognising clinical deterioration.

What is an appropriate length of time to stretch children in the ED prior to discharge?

A: After two sets of 3-4hrly inhaler/nebulisers

B: After they reach the first 3-4 hrs post last inhaler/nebuliser

C: After two sets of 3hrly

D: After 1 hour, if obs are completely normal and has had a consultant review

The correct answer is B.

BUT this is based on a randomised control trial in 1999. The most recent study in 2018 suggests that there is no benefit to 4hours vs 3hrs, and in fact 3 hrs post inhalation resulted in a reduction in length of stay. A recent retrospective analysis study in Australia looked at discharging children after 1 hour. They suggested that children that were clinically ‘well’ at 1 hour were likely to go home and if they were showing any moderate symptoms at one hour would likely need to be admitted. There is no strong evidence or recent studies, which is why there is such variation in practice. 

Under what circumstances would you choose to administer a beta agonist via nebuliser as opposed to a pMDI with a spacer?

A: When the child has become more tachycardic with worsening salbutamol induced tremor

B: In severe or life threatening asthma or when under the age of 1yrs old/learning difficulties

C: If the pMDI is ineffective

D: Some departments prefer nebulisers as it is cheaper than inhaled preparations

The correct answer is B.

Cochrane review 2013 – “Metered-dose inhalers with a spacer can perform at least as well as nebulisation in delivering beta-agonists in children with acute asthma”

Salbutamol has systemic side effects – tremor and increased pulse rate were more common when using nebulisers. SIGN/BTS guidelines state to give nebulisers in severe or life threatening asthma. Nebulisers are also preferential in very young children, or those with learning difficulties, as coordinating breathing with an inhaler can be difficult. Cost savings can be made with inhaled preparations. 

When is intubation indicated in paediatric asthma presentations?

A: When the HR > 160 OR the RR > 60

B: When you have given all first line and second line treatment and trialled NIPPV and the patient has still not improved. 

C: The child looks exhausted with worsening hypercapnia and changes in mental status. 

D: When the child has a history of fast deterioration and need for intubation

The correct answer is C.

Up to 26% of children intubated due to asthma suffer complications including pneumothorax, impaired venous return, and cardiovascular collapse because of increased intrathoracic pressure. Mechanical ventilation during an asthma exacerbation is associated with an increased risk of death and should therefore be a last resort. The decision to intubate should be based on clinical judgement as opposed to any one observation or blood result. Some variables to consider for intubation are worsening hypercapnia, patient exhaustion and changes in mental status (EMCases).

You have a 4 yr old, with two days of wheeze, coryzal symptoms and one day of increased work of breathing symptoms. You suspect that this may be viral induced wheeze. How do you manage this child?

A: Burst therapy with salbutamol. 

B: 6-10 puffs of salbutamol and reassess. If severe symptoms give oral steroids. 

C: Humidified air nebuliser and antipyretics for fever. 

D: 6-10 puffs of salbutamol and Ipratropium bromide nebuliser. If severe symptoms give oral steroids.

The correct answer is B.

At what age would it be appropriate to consider a trial of ventolin for potential viral induced wheeze? 

  • (Note – This is a good opportunity to survey your team and colleagues to see what the practice is at your local department). 
  • Regarding this grey area question, in Australian practice, some clinicians will trial salbutamol for potential viral induced wheeze if the child is 12 months or older. Other doctors may wish to trial if the child is slightly younger (e.g. from 10 months) if they have a strong family history of asthma and atopy or if they have had previous ventolin use reported by their family with good effect. The younger the child is, the less likely that the story and case is to fit viral induced wheeze.

If you are not sure if the child is presenting with asthma or viral induced wheeze, but they are displaying severe symptoms – it is advisable to give steroids. But be cautious in giving too many courses of steroids if presenting frequently to the ED.

M Balfour-Lynn (1996) Why do viruses make infants wheeze?, Archives of Disease in Childhood  74: 251-259

MO Stormon, CM Mellis, PP Van Asperen, HA Kilham (2002) Outcome evaluation of early discharge of asthmatic children from hospital: A randomized control trial, Journal of quality in clinical practise, Vol 19, issue 3, 149-154

Huay-ying Lo, Amanda Messer, Jennifer Loveless, Esther Sampayo, Robert H. Moore, Elizabeth A. Camp, Charles G. Macias and Ricardo Quinonez (2018) Discharging Asthma Patients on 3-Hour β-Agonist Treatments: A Quality Improvement Project, Hospital Pediatrics, 8 (12) 733-739

Basnet S, Mander G, Andoh J, Klaska H, Verhulst S, Koirala J (2012) Safety, efficacy, and tolerability of early initiation of noninvasive positive pressure ventilation in pediatric patients admitted with status asthmaticus: a pilot study. Pediatr Crit Care Med 13(4):393-8.

Snelson, E (2019) A simple model for understanding the causes of paediatric wheeze, Paediatrics and Child Health, Volume 29, Issue 8, Pages 365-368

DFTB – Managing acute asthma, Simon Craig (2017)

DFTB – Asthma for ambos (2016)

DFTB – Are nebulisers or spacers better for managing acute asthma (2013)

DFTB – The curious incident of the wheeze in the night

PEMBLOG – Heliox in the emergency department (2017)

EMCases – Management of acute paediatric exacerbations (2016)

BTS/SIGN British guideline on the management of asthma in children (2019)

PaediatricFOAM – ventilation strategies for the critically ill asthmatic (2019)

RCEMLearning – Arrest in asthma

gppaedstips.blogspot.com – The NYCE guideline for viral induced wheeze – Let’s clear a few things up (2019)



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The curious incident of the wheeze in the night time

Cite this article as:
Costas Kanaris. The curious incident of the wheeze in the night time, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.22330

The first rule of the DFTBquiz is that the approach to each particular case and patient is not dogma, nor is it the only way in which the case can be safely managed in our virtual ED. There are numerous ways to approach critical illness. As long as the applied clinical treatment passes both the evidenced based medicine and family litmus then we have nothing to fear apart from the disease process itself.

So how would the DFTB team at Bubbles Central Hospital approach the child with life threatening bronchospasm, altered sensorium that has a pneumothorax and an SVT?

If you missed the original question – check it out here

This has been the second most successful #pedsicu f#ridayquiz to date with >30k impressions and answers from 29 different countries! It was a complex case of common pathologies amalgamated in one patient – status asthmaticus with a pneumothorax and SVT.

We outline the DFTB team’s take on the case and how we would approach it if we had this patient in our own resus bay. Please note this is not the only way to approach the patient but rather what our consensus is as to how to prioritize clinical issues and minimize risk in this patient by using a rational, evidence-based and pharmacologically prudent approach.  There were numerous excellent answers from across the globe. Here are a few highlights…

Things to consider are:

  • What is immediately the most life-threatening pathology? The pneumothorax? The SVT? The severe bronchospasm?
  • Why does the child have lactic acidosis?
  • Is it really an SVT or is it a tachycardia, exacerbated by nebulized beta-agonists? What risks are posed by any intervention we undertake?
  • How do we minimize the risks identified above?
  • What drugs should we use for intubation and what how do we maintain anaesthesia thereafter?

1. What is immediately the most life-threatening pathology? 

It is clear that this child is at high risk of cardiorespiratory arrest if we do nothing.

Clues to that are hypoxia, hypercarbia (especially in the context of altered sensorium)[1]; air trapping to the extent where a pneumothorax has developed (a known complication of asthma)[2] and the lactic acidosis, which in this case is likely to be secondary to a combination SVT leading to myocardial hypoperfusion and the respiratory muscles tiring (more on that later).

On the ABCDEFG approach (Airway, Breathing, Circulation, Disability, Exposure, Fluids, Glucose) we are taught to approach airway first. This failsafe approach may work well in most clinical emergencies but in this case, intubating before achieving cardiorespiratory stability is likely to put the patient in an even stickier situation.  Breathing (i.e. adequate oxygenation) is likely to be the first pathology to lead to cardiorespiratory arrest. That needs to be addressed first. The SVT is likely to cause considerable instability during intubation; this is superimposed to the pre-existing high risk of adverse events that accompany life-threatening asthma[3]. So the SVT needs to be cardioverted prior to intubation if possible.

Furthermore, the risk of converting a pneumothorax to a full-blown tension pneumothorax by attempting to intubate first is significant. Most modified RSI methods include a bag and mask ventilation technique. The application of positive pressure ventilation either before or after the ETT is in place –once the patient is established on a ventilator- risks changing the nature of the pneumothorax from a simple one to a life-threatening tension-type one[4].

In this case, therefore, airway stabilization – although high on the list of priorities – should come after we have optimized breathing and circulation (unless the patient arrests beforehand).


2. Why does the child have lactic acidosis?

The latter is important to understand and differentiate in someone who has been receiving a beta-agonist.

In the context of asthma lactic acidosis may be due to overproduction and/or inadequate clearance of lactic acid. Therefore, lactic acidosis in a child with severe bronchospasm could result:-

      • if patients were in occult shock
      • if produced by tiring respiratory muscles (i.e., respiratory muscle oxygen demand outstripping oxygen supply)
      • if produced by the lung parenchyma
      • if changes in glycolysis were caused by beta-agonist administration.
      • lactic acid could also be under metabolized by the liver

In our case the patient did not receive any IV salbutamol and only a couple of nebulizers; pharmacogenic lactic acidosis is therefore unlikely.

Much more likely is a lactic acidosis as a result of tiring respiratory and cardiac muscles. The latter is especially important to recognize in the context of an SVT. The myocardium perfuses during diastole[6]. If the HR is 300, the diastolic time is minimal, so there isn’t much time for the myocardium to be adequately perfused.

Tired respiratory and cardiac muscles make for a very high-risk intubation process.


3. Is it really an SVT or is it a tachycardia, exacerbated by nebulized beta-agonists?

It is tempting to think that such a significant tachycardia has been caused by a combination of factors: the patient is hypovolaemic, the patient is stressed, we gave him a couple of salbutamol nebs – and so on.

How can we differentiate a sinus tachycardia from an SVT?

Most textbooks will empirically state if the HR is >210-220 then the rhythm’s is more likely to be SVT, if it is <200-210 then it is likely to be sinus tachycardia.

This is loosely true but not always, especially in the context of paediatrics where we have different HR norms for each age.

Beat-to-beat variability is important in differentiating SVT from sinus tachycardia. Whilst in SVT each (P) QRST complex looks the same as the one after it, in sinus tachycardia each PQRST complex is different. A 12 lead ECG will help you ascertain this more accurately.

The presence of P waves is another determining factor.  A true SVT oughtn’t to have P waves preceding the QRS complex, whereas in a sinus tachycardia a P wave is usually present.  This is often tricky to differentiate in practice, especially if the ECG or cardiac monitors are tuned onto real-time speed. The best trick to apply is to slow the monitors down enough. This will slow down the speed of the PQRST complexes, allowing us to better visualize the P wave.

Vagal manoeuvers and pharmacological therapy if there is uncertainty about the cardiac rhythm is poor practice and should be avoided.  Cardiac output equals stroke volume times heart rate (CO= SVxHR). If we try to slow down the heart in the context of very fast sinus tachycardia with drugs or by stimulating the vagus nerve we will drop the cardiac output and put the patient at risk of a cardiac arrest.  We always need to be sure of the rhythm before any intervention.

If you are still uncertain, a reasonably safe bedside test would be to give 10ml/kg fluid bolus (ideally balanced solution) and keep an eye on the monitor whilst it’s infusing. If it is an SVT the HR will not budge. If it is sinus tachycardia, you are much more likely to see some slowing down of the rate.


4. What risks are posed by any intervention we undertake?

The risks of intubating someone with pneumothorax have been outlined above.

PPV can change a stable, small pneumothorax into a life-threatening tension pneumothorax. This dictates that we should ideally put a temporary chest drain in to decompress the thorax prior to intubation.

The other risk in optimizing breathing in this scenario is an exacerbation of the SVT by giving IV bronchodilating agents that are known to have a potent chronotropic effect. Both aminophylline [7] and salbutamol [8] are known to be chronotropic, but evidence would suggest that aminophylline causes less of a chronotropic effect than salbutamol[9]. With that in mind, loading with IV aminophylline in order to break the bronchospasm spiral would be the best (or least bad) option.

Also worth noting that MgSO4 is a potent vasodilator, so if we intend to use it in this setting to optimize bronchodilation it needs to be done as a low infusion (over 25-30 minutes)

The risks we may encounter whilst in improving circulation prior to intubation are twofold.

Firstly, in addressing cardioversion, adenosine is the most commonly used agent in treating SVT pharmacologically. A known side effect of adenosine, however, is bronchospasm[10].  There is little high-quality evidence to assess the effects of adenosine on asthmatic airways. What little evidence there is (and the evidence is nearly all from adult subjects) would suggest that adenosine is safe to use in patients with reactive airways[11],[12].

Secondly, this patient is likely to have a degree of dehydration. This degree of tachypnoea and work of breathing increases fluid loss through the respiratory tract. The degree of tachycardia also suggests a hyper-metabolic demand, again suggesting increased fluid consumption. It would, therefore, be prudent to give this patient some volume prior to intubation.  As the patient already has metabolic acidosis,  (ab)normal saline would be a poor choice. The chloride content is likely to increase chloride levels leading to a worsening metabolic acidosis [13], which in turn would worsen myocardial contractility [14],[15]. Balanced solutions (Plasmalyte 148 or Hartmann’s) are by far more physiologically appropriate and unlikely to exacerbate the metabolic acidosis [16],[17] and therefore preferred in this instance.


5. How do we minimize the risks identified above?

We have alluded to a lot of the steps in the analysis above. The main objective is to optimize oxygenation and primum non-nocere.

Bronchodilation prior to intubation is key. In this case, it is reasonable to go “all-out” and load with IV aminophylline, IV Hydrocortisone, IV Magnesium and a triple agent nebulizer (repeat if needed) consisting of salbutamol, ipratropium, and adrenaline (croup dose) to try and minimize air trapping by opening up the airways.

A temporary chest drain is important. This will help with pre-intubation oxygenation and reduce the risk of a peri-intubation tension pneumothorax from developing.

Cardiovascular stabilization is also important prior to intubation. Volume resuscitation prior to intubation is best done with a balanced solution (as outlined above) and –if anaemic- possibly blood as that would help with the overall oxygen-carrying capacity and give the patient more reserve. It is important to remember that this should be done in 10ml/kg aliquots because a high proportion of children with SVT will have concomitant congenital anatomical abnormalities. Give the fluid, assess response, check for rhonchi and hepatomegaly, and repeat as necessary. It is possible that the patient may still need cardiovascular support after intubation.

Which inotrope is best will be dictated by whether or not we have managed to successfully cardiovert (by vagal maneuvers first, by incremental doses of adenosine second and by DC cardioversion third). The inotropes need to be pre-drawn, prior to intubation so that we can start them quickly. This is not a scenario where we should be playing catch-up and preparation is key.

IV adrenaline would be a strong favorite in the usual asthmatic, not least because it has potent bronchodilatory effects and is reasonably safe to use in asthmatics[18]. If we have managed to stop the SVT then there would be a strong argument to favour this.  Adrenaline, of course, is also a potent chronotrope, so we should; on balance avoid it in someone with SVT. Noradrenaline is the least chronotropic out of our inotrope choices, so if we are still in SVT or we think that the patient is at high risk of reverting back into SVT then it would, on balance, be our best choice. Have a low threshold for inserting an IO if you don’t have enough large-bore access.


6. What drugs should we use for intubation and what how do we maintain anaesthesia thereafter?

 There is a long-standing truism in the art of rapid sequence intubation that says, “there is no such thing as a cardiostable induction”. This is especially true in the intubation process of critically ill children. All induction agents tend to vasodilate and cause a blood pressure drop. Couple that with the vagal stimulation caused by the laryngoscope and you can see why RSI is tricky business.

Arguably the least cardio-unstable combination of drugs in this setting would be ketamine  (1-2mg/kg),fentanyl (1mcg/kg), and rocuronium (1-2mg/kg). Ketamine has the added benefit of being a bronchodilator so it would definitely help in reducing the bronchospasm[19].

Intubating using sevoflurane may also be attractive for experienced anesthetists, not least because of the potent bronchodilatory effect that it can offer us[20]. This would still be my second choice however, because of how much vasodilation and blood pressure drop it may cause.

Always be prepared for adverse events during intubation. In this case, our chest drain needs to be in first, we need some inotropes pre-drawn as well as some volume in case the BP drops. A favorite trick of mine is using dilute adrenaline as a bolus to improve BP or HR or both should they drop during intubation.

The dilution is essentially tenfold of the resuscitation dose. Take the resus dose, dilute it with 10 ml of saline and you can bolus the eventual solution in 1ml aliquots. This is a superior drug when compared to commonly used atropine as it addresses also the BP drop and not just the HR drop.

Maintenance of anaesthesia is often with continuous infusion of morphine and midazolam. In this case, those agents would not be the best choice. Morphine is known to increase histamine release and is therefore likely to exacerbate bronchospasm and peripheral vasodilatation.  Fentanyl, as a continuous infusion, is proven to cause less histamine release and is, therefore, a superior choice in this case[21].

Coupling the fentanyl with a ketamine infusion (instead of midazolam) would also be preferable, mainly because of ketamine’s bronchodilatory effects. For doses /rates and dilutions of these pharmacological agents fill in and print the drug chart on crashcall.net or the one provided by your regional paediatric critical care transport team.

 

So what plan would go up on the PED resus board?

  1. Optimize B and C first. Prepare Airway trolley  (including 4, 4.5 and 5 cuffed ETT) and draw up 10ml aliquots of Plasmalyte dilute adrenaline. Draw up noradrenaline and adrenaline for infusions if needed.
  2. Break the bronchospasm cycle. IV aminophylline, slow IV MgSO4, triple neb (adrenaline, salbutamol, ipratropium). Temporary chest drain –and prepare for a more robust one after intubation.
  3. Confirm rhythm. 10ml/kg fluid volume, vagal maneuvers, incrementally increasing doses of adenosine until Cardioversion 100mcg/kgè200mcg/kgè 300mcg/kgè500mcg/kg. If adenosine fails for DC Cardioversion. Ideally prior to intubation.
  4. 1-2mg/kg ketamine, 1mcg/kg fentanyl, 1-2mg/kg Rocuronium; maintain anaesthesia with ketamine and fentanyl infusions (crashcall.net doses/rates)
  5. Empirical cover, include cover for atypical infections: Ceftriaxone + Clarithromycin. If flu possible consider Oseltamivir.
  6. Avoid 0.9%Saline, 10ml/kg aliquot of Plasmalyte or Hartman’s, if anaemic consider blood. Reassess after every bolus (liver size and rales).
  7. Keep an eye, likely to rise (stress response, steroids, salbutamol) unlikely to need treatment even if high.

Remember, this is just the DFTB team’s approach. There are numerous ways to skin a cat; if you have an alternative way we are keen to hear it!

References

[1] Holley, Anthony D., and Robert J. Boots. “management of acute severe and near‐fatal asthma.” Emergency Medicine Australasia 21.4 (2009): 259-268.

[2] Porpodis, Konstantinos, et al. “Pneumothorax and asthma.” Journal of thoracic disease 6.Suppl 1 (2014): S152.

[3] Zimmerman, JANICE L., et al. “Endotracheal intubation and mechanical ventilation in severe asthma.” Critical care medicine 21.11 (1993): 1727-1730.

[4] Bacon, A. K., et al. “Crisis management during anaesthesia: pneumothorax.” BMJ Quality & Safety 14.3 (2005): e18-e18.

[5] Forsythe, Sean M., and Gregory A. Schmidt. “Sodium bicarbonate for the treatment of lactic acidosis.” Chest 117.1 (2000): 260-267.

[6] Heusch, G. “Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents.” British journal of pharmacology 153.8 (2008): 1589-1601.

[7] Urthaler, Ferdinand, and Thomas N. James. “Both direct and neurally mediated components of the chronotropic actions of aminophylline.” Chest 70.1 (1976): 24-32.

[8] Crane, J. et al “Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.” Thorax 44.2 (1989): 136-140.

[9] Morice, A. H., et al. “A comparison of the ventilatory, cardiovascular and metabolic effects of salbutamol, aminophylline and vasoactive intestinal peptide in normal subjects.” British journal of clinical pharmacology 22.2 (1986): 149-153.

[10] Bennett-Guerrero, Elliott, and Christopher C. Young. “Bronchospasm after intravenous adenosine administration.” Anesthesia & Analgesia 79.2 (1994): 386-388.

[11] Burki, Nausherwan K., Mahmud Alam, and Lu-Yuan Lee. “The pulmonary effects of intravenous adenosine in asthmatic subjects.” Respiratory research 7.1 (2006): 139.

[12] Terry, Polly, and Gail Lumsden. “Using intravenous adenosine in asthmatics.” Emergency Medicine Journal 18.1 (2001): 61-61.

[13] Kellum, John A. “Saline-induced hyperchloremic metabolic acidosis.” Critical care medicine 30.1 (2002): 259-261.

[14] Cingolani, Horacio E., et al. “Depression of human myocardial contractility with “respiratory” and “metabolic” acidosis.” Surgery 77.3 (1975): 427-432.

[15] Williamson, John R., et al. “Effects of acidosis on myocardial contractility and metabolism.” Acta medica scandinavica199.S587 (1976): 95-112.

[16] Bellomo, Rinaldo, et al. “Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults.” Jama 308.15 (2012): 1566-1572.

[17] Chowdhury, Abeed H., et al. “A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and plasma-lyte® 148 on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers.” Annals of surgery 256.1 (2012): 18-24.

[18] Putland, Mark, Debra Kerr, and Anne-Maree Kelly. “Adverse events associated with the use of intravenous epinephrine in emergency department patients presenting with severe asthma.” Annals of emergency medicine 47.6 (2006): 559-563.

[19] Allen, Joseph Y., and Charles G. Macias. “The efficacy of ketamine in pediatric emergency department patients who present with acute severe asthma.” Annals of emergency medicine 46.1 (2005): 43-50.

[20] Schutte, D., et al. “Sevoflurane therapy for life-threatening asthma in children.” British journal of anaesthesia 111.6 (2013): 967-970.

[21] Rosow, Carl E., et al. “Histamine release during morphine and fentanyl anesthesia.” Anesthesiology 56.2 (1982): 93-96.