Padmanabhan Ramnarayan. High flow therapy – when and how?, Don't Forget the Bubbles, 2021. Available at:
https://doi.org/10.31440/DFTB.31730
Isn’t nasal high flow just a fancy name for plain old high flow oxygen? Or is it CPAP-lite? For a therapy that has become so popular in less than a decade, amazingly, there is more opinion sloshing around than proper scientific evidence…
OK, back up, what is Nasal High Flow therapy?
Nasal high flow therapy (NHF), aka high flow nasal cannula therapy (HFNC), is a non-invasive mode of respiratory support, involving the delivery of heated (to 37° C) and humidified (to nearly 100% relative humidity) gas (oxygen and/or medical air) through nasal cannulae at high gas flow rates. What is a “high” gas flow rate is still not uniformly defined (some studies say >2 L/min and others >4 L/min). In physiological terms, to provide the true benefits of “high flow”, the gas flow rate should exceed the patient’s maximal peak inspiratory flow rate (roughly 8-10 x normal minute ventilation).
Makes sense, but what is a child’s peak inspiratory flow rate?
Short answer – it changes according to the age and the extent of respiratory distress. For example, a 4 kg baby breathing at 40 breaths/min and inhaling a tidal volume of 5 ml/kg (=20 ml) would have a minute ventilation of 0.8 L/min and a peak inspiratory flow (PIF) rate of nearly 3 L/min. However, the same infant would have a much higher PIF in respiratory distress. Matching the maximal PIF rate by aiming for roughly 8-10 x normal minute ventilation (in this case, 8-10 x 0.8 L/min = 7-8 L/min) is the key principle of NHF therapy. NB: Magically, the 8 L/min flow rate in this baby is also 2 L/kg/min (more on that later!)
Got it. But when should I start NHF in the ED?
Case 1. A previously healthy 4-month old infant is seen in the emergency department with a two-day history of coryza and poor feeding. On examination, he has mild/moderate subcostal recession and a respiratory rate of 60 bpm. His oxygen saturation in room air is 89%. Would you start nasal high flow?
This baby most likely has mild viral bronchiolitis and the main question is whether to start standard oxygen therapy (SOT) via nasal cannulae or NHF. The most useful clinical outcomes we are interested in are transfer to paediatric intensive care (PICU) and the need for endotracheal intubation.
What does the evidence say?
A recent systematic review (Lin J et al. Arch Dis Child 2019) is an obvious starting point. For the outcome of transfer to PICU, only two RCTs were included (Franklin et al. NEJM, 2018; Kepreotes et al. Lancet 2017). The overall risk ratio was 1.30 (95% CI 0.98, 1.72) indicating no significant difference between NHF and SOT, although there was a tendency to favour SOT.
Similarly, only two RCTs were included for the outcome of intubation (Franklin et al. NEJM, 2018; Yang et al. Chinese Pediatric Emergency Medicine, 2017). The overall risk ratio was 1.98 (95% CI 0.60, 6.56), again with no significant difference between NHF and SOT. So, not much joy from the systematic review…
Considering that Franklin et al dominated the systematic review in terms of sample size, it is useful to look at this RCT in a bit more detail, from a PICO point of view as well as the flow of patients through the RCT.
Population: Infants <12 months of age with bronchiolitis and needing supplemental oxygen
Intervention: NHF at 2 L/kg/min
Control: Standard oxygen therapy
Outcome: Escalation of care due to treatment failure (composite outcome)
A few reflections on the outcomes of infants in this RCT: although nearly double the number of infants randomised to SOT “failed treatment” compared to NHF, it is notable that over 75% of infants randomised to SOT did not “fail”; the majority of those who did “fail” SOT were rescued by NHF; and since NHF “failure” automatically led to PICU transfer, in effect, more infants were transferred to PICU in the NHF group than in the SOT group (12% vs 9%). Essentially, this RCT could be considered a trial of ‘immediate’ NHF versus ‘rescue’ NHF, as covered by us here previously.
Bottom line: There is no advantage to starting NHF as first-line therapy in an infant with mild bronchiolitis. A more clinically and cost-effective strategy would be to use NHF as ‘rescue’ therapy when standard oxygen therapy has failed.
Case 2. An ex-prem born at 24 weeks gestation, now 4 months old, is seen in the emergency department with a 24-hour history of coryza and cough. On examination, he has moderate/severe subcostal recession and a respiratory rate of 80 bpm. His oxygen saturation in room air is 85%. Would you start nasal high flow?
This baby is much sicker, with significant past medical history, and most likely has moderate/severe bronchiolitis. Would NHF be more useful as first-line therapy in this infant, where previously nasal CPAP would have been an option – can NHF be used as ‘CPAP-lite’? A really useful clinical outcome to focus on is endotracheal intubation.
What does the evidence say?
Lin et al summarise the evidence in their recent systematic review. For the outcome of intubation, 4 RCTs were included, but the total number of patients included were low (n=264). Intubation rates were identical in the NHF and CPAP groups (5.3%), with a risk ratio of 0.96 (95% CI 0.35, 2.61). So, there is not much evidence to support the use of NHF compared to CPAP, although quite notably, the rate of adverse events was lower in the NHF group (8% vs 21%).
Bottom line: There is no clinical advantage to starting NHF as first-line therapy in an infant with moderate to severe bronchiolitis to avoid intubation. However, its adverse event profile and tolerability by infants might make NHF more appealing as first-line therapy.
When should I start NHF in the HDU?
Case 3: A 5-year old boy with cerebral palsy and epilepsy is admitted to the paediatric HDU bed with fever, cough and respiratory distress. On examination, he has moderate subcostal and intercostal recession and a respiratory rate of 45 bpm. His oxygen saturation in room air is 88%. Would you start nasal high flow?
In this older child with a complex past medical history, is starting NHF, compared to either standard oxygen or CPAP, beneficial in terms of avoiding the need for endotracheal intubation?
What does the evidence say?
A recent systematic review (Luo J et al. Journal of Pediatrics, 2019) is an obvious starting point. In the comparison of NHF versus SOT, 5 RCTs were included, although 2 were focussed on bronchiolitis (previously covered – Franklin et al and Kepreotes et al). The other 3 RCTs were small (Chisti et al. Lancet, 2015; Ergul et al. Eur J Pediatrics, 2018; Sittikharnka et al. Indian J Crit Care Med 2018) with just 300 patients in total. The overall risk ratio for intubation from these 3 studies alone (calculated specifically for this post) was 0.72 (95% CI 0.38, 1.36). Similarly, in the comparison of NHF versus CPAP, 4 RCTs were included but 2 were in bronchiolitic infants (covered earlier). The other two RCTs (Ramnarayan et al. Crit Care 2018; Chisti et al. Lancet 2015) included just 187 children. The overall risk ratio for intubation based on these two RCTs (calculated for this post) was 2.14 (95% CI 0.93, 4.92) indicating a tendency for a higher intubation rate with NHF in older children.
Bottom line: In an older child, intubation was not less frequent when NHF was used compared to SOT as first line therapy. There was a tendency for NHF to be associated with a higher intubation rate compared to CPAP.
Great – what is the best way to provide NHF?
Starting gas flow rate
Milesi et al showed in physiological studies in infants aged <6 months with bronchiolitis that the work of breathing is reduced considerably when the gas flow rate is set at nearly 2 L/kg/min. In their cohort of 21 infants (mean weight 4.3 kg), the measured work of breathing was lowest at a flow rate of 7 L/min (compared to 1, 4 and 6 L/min). Similarly, in children up to the age of 3 years with pneumonia, work of breathing was reduced by nearly 20% at a flow rate of 1.5 L/kg/min compared to 0.5 L/kg/min (Weiler et al. Journal of Pediatrics 2017). Usual adult flow rates range from 50-60 L/min.
In summary, the optimal gas flow rate does not increase in a linear fashion with increasing age/weight, instead it goes from nearly 2 L/kg/min in infancy to nearly 1 L/kg/min in young adults.
RCTs of different starting flow rates
There have been two RCTs comparing NHF flow rates in bronchiolitis (Yurtseven A et al. Ped Pulm 2019; Milesi et al. Intens Care Med 2018). In the former, 1 L/kg/min (n=88) was compared to 2 L/kg/min (n=80) in infants <24 months with clinical severe bronchiolitis presenting to the emergency department. The primary outcome was ‘treatment failure’ within 24 hours. There was no significant difference in treatment failure between the two flow rates (1 L/kg/min: 11.4%; 2 L/kg/min: 10%). The second RCT compared 2 L/kg/min (n=142) with 3 L/kg/min (n=144) in infants aged <6 months with moderate/severe bronchiolitis. The primary outcome was treatment failure within 48 hours. There was no significant difference in treatment failure between the two groups (2 L/kg/min: 38.7%; 3 L/kg/min: 38.9%).
A useful chart with suggested starting flow rates based on weight is used in the ongoing FIRST ABC clinical trial of NHF versus CPAP.
Nasal cannula size
There are different nasal cannula sizes available based on the manufacturer. The general rule of thumb is that the cannula prongs should be no more than 50% of the diameter of the nostril to avoid inadvertent occlusion of the nasal passages. It is also advisable to start the gas flow rate at a low rate and then increase gradually over 10-15 min to avoid patient discomfort. Pacifiers may be useful in babies to prevent mouth opening.
Weaning NHF
There are no RCTs comparing weaning strategies for NHF. Clinical practice is also highly variable – in a global survey of practice in over 1000 PICU professionals by Kawaguchi et al, 68% weaned the FiO2 first to a threshold value (e.g. 0.40) and then weaned the flow rate gradually, 11% weaned the FiO2 first to a threshold value (e.g. 0.40) and then stopped NHF, and 4% weaned the flow rate alone without weaning the FiO2. The FIRST ABC RCT algorithm for the weaning of NHF provides a weight-based approach to a one-step weaning process and suggested clinical thresholds for weaning and stopping NHF.
The take homes
- Nasal high flow is a form of non-invasive respiratory support that sits somewhere between standard oxygen therapy and nasal CPAP.
- In infants with mild bronchiolitis, there is no clinical (or cost) benefit in starting NHF as first-line treatment – rather, NHF is best used as a ‘rescue’ therapy after standard oxygen.
- In infants with moderate/severe bronchiolitis, NHF may be a useful first-line therapy owing to its ease of use and since it is better tolerated by infants, however there is no clinical benefit compared to nasal CPAP.
- In older children with respiratory failure, there is little RCT evidence to guide practice – however, there is no clear benefit of starting NHF over and above standard oxygen. NHF may be associated with a higher intubation rate compared to CPAP in older children.
- There is no RCT evidence to support either 1, 2 or 3 L/kg/min NHF flow rates in infants with bronchiolitis; however, physiological evidence suggests that nearly 2 L/kg/min is associated with reduction in work of breathing. Suitable flow rates in older children approximate 1.5 L/kg/min and in young adults, 1 L/kg/min.
- There is no RCT evidence to support one way of weaning over another – the most common practice seems to be to reduce FiO2 to below 0.40, followed by a reduction in the NHF flow rate.
- Ongoing RCTs such as the FIRST ABC trial will help address the question whether NHF is non-inferior to CPAP in critically ill children.
The 47th Bubble Wrap
Currie, V. The 47th Bubble Wrap, Don't Forget the Bubbles, 2021. Available at:
https://dontforgetthebubbles.com/the-47th-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 safety profile of ceftriaxone
Zeng, L., Wang, C., et al., (2020) Safety of ceftriaxone in paediatrics: a systematic review. Archives of Disease in Childhood. Oct;105(10):981-985. doi: 10.1136/archdischild-2019-317950
What’s it about?
Ceftriaxone is one of the most commonly prescribed antibiotics for children. It is a broad spectrum third generation cephalosporin, used as a first line empirical agent for meningitis, sepsis and useful against many bacterial infections. It has an elimination half-life of 8 hours and can be given once every 24 hours IV or IM, giving us options when that cannula is particularly tricky! Whilst it is well known that using ceftriaxone in the newborn is contraindicated due to biliary sludging, the authors of this paper delved into the literature to identify other adverse reactions (ADRs) to ceftriaxone.
What did they do?
The authors performed systematic searches across several databases looking for studies to evaluate the type of ADR, the incidence of ADRs in patients aged 0 – 18 years old and to identify any potential risk factors for serious ADRs. A total of 112 studies were identified (22 RCTs, 61 case reports, 19 prospective studies, 7 retrospective studies, 2 case series and 1 case control study) which reported on ADRs of ceftriaxone use (although it was not a primary outcome measurement in any of the studies).
Looking at the RCTs, prospective and retrospective studies, gastrointestinal side effects were the most common ADR (specifically, diarrhoea). The second most common ADR identified amongst these studies was hepatobiliary (biliary sludging and cholelithiasis). These ADRs were all transient, and usually self-resolved after cessation of ceftriaxone. The case reports and case studies identified the more serious ADR of immune haemolytic anaemia, which carries a risk of death, especially for patients with an underlying diagnosis of sickle cell disease.
Clinically Relevant Bottom Line:
Transient gastrointestinal side effects are generally tolerable, and we should closely monitor patients for evolving symptoms of gallstones. Most importantly, we should be mindful and cautious when prescribing ceftriaxone in patients with underlying haematological conditions such as sickle cell anaemia, due to the uncommon but significant risk of immune haemolytic anaemia. Ceftriaxone is really a great antibiotic, and as long as we remember the clinical spectrum of ADRs, we will not cause significant patient harm.
Reviewed by: Tina Abi Abdallah
Article 2: Kawasaki Disease vs Septic Shock: Early Differentiating Features Despite Overlapping Clinical Profiles
Power A, Runeckles K, Manlhiot C, Dragulescu A, Guerguerian AM, McCrindle BW. Kawasaki Disease Shock Syndrome Versus Septic Shock: Early Differentiating Features Despite Overlapping Clinical Profiles. J Pediatr. 2020 Dec 5:S0022-3476(20)31482-7. doi: 10.1016/j.jpeds.2020.12.002. Epub ahead of print. PMID: 33290811.
What’s it about?
According to literature around 6-7% *of patients with Kawasaki disease present with shock and this can provide a challenge in differentiating Kawasaki disease from septic shock. This paper looks to compare clinical features, resuscitative measures and haemodynamic response to treatment between those presenting with Kawasaki disease shock syndrome and children with septic shock.
*Kanegaye JT, Wilder MS, Molkara D, Frazer JR, Pancheri J, Tremoulet AH, et al. Recognition of a Kawasaki Disease Shock Syndrome. Pediatrics 2009;123:e783-9.
What did they do?
This was a retrospective chart review of patients under the age of 18 over a 10-year period admitted to a tertiary centre in the USA. The charts of children who met the criteria for Kawasaki disease shock syndrome (as defined by the American Heart Association) were analysed and children meeting the criteria for septic shock were used as controls. Over the 10-year period >1000 children were admitted to the centre with Kawasaki disease. Of these 9 met the criteria for Kawasaki disease shock syndrome. They were case matched with 18 controls who were admitted with septic shock.
The study found that children with Kawasaki disease shock syndrome were less likely (1 in 9) to have an underlying significant medical illness than the septic shock group (11 in 18). All the patients in the Kawasaki group had at least one of the five classic features of Kawasaki disease at presentation (rash, conjunctivitis, mucous membrane changes, cervical lymphadenopathy and extremity changes). With rash found in 7 of 9 of the patients either at presentation or during the admission. 5 in 9 of the Kawasaki disease cohort had cardiac involvement with zero of the control group with any cardiac involvement.
The length of stay for children in the Kawasaki disease shock syndrome group was a median of 9 days vs 28 days in the septic shock group, with no difference found in ICU length of stay. Biochemical markers were compared, and this study found a lower platelet count (median 140 vs 258) in the Kawasaki group. Interestingly in children with Kawasaki disease shock syndrome the duration of illness prior to admission was much longer (9 days vs 3 days) than the control group.
There have been no studies that directly compare children with Kawasaki disease shock syndrome and septic shock, so this acts as a starting point. However, it is a very small cohort (only 9 patients out of >1000 presentations of Kawasaki disease with Kawasaki shock syndrome); perhaps a multi- centre trial within a network could be done to increase the numbers.
Clinically Relevant Bottom Line:
This study has found that when compared to children with septic shock children with Kawasaki disease shock syndrome are more likely to have a lower platelet count on admission, a longer duration of illness prior to admission, cardiac involvement if an echo is performed and have a longer stay in hospital. All the patients in this study had at least one of the classic features of Kawasaki disease with rash being the most common here. As clinicians who review these children at the front door perhaps a child with a rash and low platelets fever >5 days will continue to make us think about Kawasaki disease.
Reviewed by: Vicki Currie
Article 3: Is it necessary to evaluate urinary tract infection in children with lower respiratory tract infection?
Kim JM, Koo JW, Kim H-B. Is it necessary to evaluate urinary tract infection in children with lower respiratory tract infection? Journal of Paediatrics and Child Health. 2020 Dec;56(12):1924-1928
What’s it all about?
Lower respiratory tract infections (LRTIs) and urinary tract infections (UTIs) are common childhood infections that previous literature has reported to have a concomitance rate of 3 to 10 per 100 children. While LRTIs are often self-limiting viral infections, UTIs are often caused by a bacterial source that can have long term implications if not adequately treated.
What did they do?
This was a retrospective review of 1574 patients’ medical records under 36 months of age who were hospitalised for a LRTI over a 2 year period in a South Korean hospital. 278 of patients had a fever and underwent a subsequent urine evaluation performed either by catheterisation (<24mo) or voided urine (24-36mo).
Patients with a congenital airway or kidney disease, absence of fever at presentation or whose parents refused or failed to undergo a urinalysis were excluded from the analysis.
The overall prevalence rate of a concomitant UTI with LRTI in this population was 1 in 10 in children <36mo and 13 in 100 in children <24mo. Mean age was significantly younger in the UTI group 7 months vs 12 months in the non UTI group. There was a greater prevalence rate of UTIs in boys (n=23) compared to girls (n=7). The most common organism cultured in the UTI group was Escherichia coli which were all treated with a third-generation cephalosporin. The positive rate of virus detection was 93.3% in the UTI group, and 89.9% in the non-UTI group. Most frequently detected co-infections were adenovirus, rhinovirus, and RSV.
The Bottom Line:
LRTIs and UTIs are common childhood infections that have up to a 1 in 10 concomitance rate. A child presenting with a LRTI and concomitant UTI may present to ED with early respiratory and non-specific symptoms of a UTI (fever, lethargy and irritability), which may lead clinicians to presume a respiratory source of infection and not perform or delay a urinalysis. Hence a diagnosis of an underlying UTI may be missed. Failure to diagnose and promptly treat an underlying UTI can lead to renal morbidity including renal scars, hypertension and chronic kidney disease. Considering the ease of diagnosing and treating a UTI, this study further reiterates the importance of excluding a UTI in children with LRTIs under 36 months of age, especially of male gender. However, given the nature of this single centre study in South Korea, these findings cannot be generalised to a global population and must be taken in context to the population you encounter in clinical practice.
Reviewed by: Emma Chan
Article 4: Why don’t kids get sick with COVID-19?
Zimmermann P, Curtis N., Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections Arch Dis Child 2020;0 1-11
What’s it about?
A review article analyzing the possible mechanisms for reduced severity of COVID-19 in paediatric patients. The debate about if children have a lower rate of COVID-19 infection continues but it is known that children are less severely affected (in contrast to other respiratory viruses). This appears to be true even in paediatric patients with immune suppression or preexisting conditions e.g. IDDM. What we don’t know is why. The authors look at the evidence for multiple hypotheses but the two they favor are:
1) Age related endothelial damage and increased coagulability. This fits the clinical profile of COVID-19 which features endotheliitis, micro thrombi, thrombotic complications and vasculitic skin manifestations. It could also explain COVID-19 being more severe in conditions which damage the endothelium e.g. hypertension and diabetes.
2) Age related changes to the immune system. There is a decline in innate and adaptive immunity in the elderly compared with children who have not gone through this decline. The chronic proinflammatory state (which predisposes to the cytokine storm seen in severe COVID-19) increases with age. Additionally the authors hypothesize that the effect of chronic CMV infection on T-cells may explain the worsening of COVID-19 with age.
The authors concluded that these were the only two hypotheses which fit with the age-gradient in COVID-19 with mortality and morbidity rising steeply after 60-70.
The bottom line
If we could figure the ‘magic formula’ protecting children against severe COVID-19 we could use this to target treatment in adults. However, this paper is very much exploring theories and cannot yet be extended to clinical treatments.
The interplay between a lack of endothelial damage, lack of propensity to hyper-coagulation and their not yet declined immune system are most likely to protect children from severe COVID-19 infection.
Reviewed by: Sarah Reynolds
Article 5: A Gut Feeling: Abdominal Symptoms as an Initial Presentation of EVALI
Christel Wekon-Kemeni, MD, Prathipa Santhanam, MD, Pallav Halani, MD, Lauren Bradford, MD, Ceila E. Loughlin, MD.A Gut Feeling: Abdominal Symptoms as an initial presentation of EVALI, Paediatrics Volume 147, number 1, January 2021.
What’s it about?
Vaping or electronic cigarette use associated lung injury (EVALI) is a syndrome resulting from electronic cigarette use which causes predominantly respiratory symptoms, such as shortness of breath.
This case report describes an American 13-year-old male presenting, on two occasions primarily with abdominal symptoms of pain, nausea and vomiting. Initially, he was managed as a case of gastroenteritis, and had been noted to have borderline saturations. Initial abdominal CT report described bilateral lung pathology (lower lobe consolidation and atelectasis) in addition to mild jejunal loop thickening. However, after a second admission with similar symptoms plus raised inflammatory markers and fever, further workup was commenced.
Repeat abdominal CT excluded appendicitis and evidence of inflammatory bowel disease. CXR revealed bilateral changes and a Thoracic CT identified multifocal ground-glass changes and infiltrates bilaterally with scattered septal thickening and dependent bibasal opacities.
Following a review of the patient by the respiratory team, a year long history of e -cigarette use preceding this patient’s symptoms was discovered, identifying EVALI as the potential diagnosis.
The patient was started on intravenous methylprednisolone which, following an improvement in all symptoms, was converted to a course of oral corticosteroids. Repeat thoracic CT one month following discharge showed almost complete resolution of the initial changes.
Why does it matter?
EVALI is a relatively new syndrome, mostly documented in North America, with the potential to increase in prevalence as we see the popularity of e-cigarette use continuing to rise.
Given this patient’s initial symptoms of nausea and vomiting, detailed smoking history to include e-cigarette use may not have been taken. Thus, a workup for abdominal pathology was justifiably completed. However, considering published case reports of EVALI describing nausea and vomiting as common symptoms, this diagnosis should still be considered in patients presenting without respiratory involvement initially. The data available describing EVALI in the paediatric population is sparse, nevertheless in adult’s progression to respiratory failure requiring invasive ventilatory support is reported.
Clinically Relevant Bottom Line:
Although challenging, obtaining an accurate smoking history to include e-cigarette use in young people is important for the consideration of EVALI as a diagnosis. We still don’t completely understand the pathophysiology of e-cigarettes, or how much damage they are causing to the young people we see who smoke them, but remembering to ask about this as part of your history is a step we can take to improve knowledge and understanding.
Reviewed by: Joshua Tulley