European Journal of Clinical Pharmacology (2022) 78:1613–1622

https://doi.org/10.1007/s00228-022-03374-3

REVIEW

Use of ketamine in patients with refractory severe asthma

exacerbations: systematic review of prospective studies
Luigi La Via1,2 · Filippo Sanfilippo1 · Giuseppe Cuttone2 · Veronica Dezio1,2 · Monica Falcone3 · Serena Brancati4 ·
Claudia Crimi5 · Marinella Astuto1

Received: 12 April 2022 / Accepted: 17 August 2022 / Published online: 26 August 2022
© The Author(s) 2022

Abstract
Purpose Asthma is a heterogeneous disease with a wide range of symptoms. Severe asthma exacerbations (SAEs) are char-
acterized by worsening symptoms and bronchospasm requiring emergency department visits. In addition to conventional
strategies for SAEs (inhaled β-agonists, anticholinergics, and systemic corticosteroids), another pharmacological option is
represented by ketamine. We performed a systematic review to explore the role of ketamine in refractory SAEs.
Methods We performed a systematic search on PubMed and EMBASE up to August 12th, 2021. We selected prospective
studies only, and outcomes of interest were oxygenation/respiratory parameters, clinical status, need for invasive ventilation
and effects on weaning.
Results We included a total of seven studies, five being randomized controlled trials (RCTs, population range 44–92 patients).
The two small prospective studies (n = 10 and n = 11) did not have a control group. Four studies focused on adults, and three
enrolled a pediatric population. We found a large heterogeneity regarding sample size, age and gender distribution, inclu-
sion criteria (different severity scores, if any) and ketamine dosing (bolus and/or continuous infusion). Of the five RCTs,
three compared ketamine to placebo, while one used fentanyl and the other aminophylline. The outcomes evaluated by the
included studies were highly variable. Despite paucity of data and large heterogeneity, an overview of the included studies
suggests absence of clear benefit produced by ketamine in patients with refractory SAE, and some signals towards side effects.
Conclusion Our systematic review does not support the use of ketamine in refractory SAE. A limited number of prospective
studies with large heterogeneity was found. Well-designed multicenter RCTs are desirable.

Keywords Bronchospasm · Asthma · Inflammation · Fentanyl · Aminophylline · Mechanical ventilation

Introduction

Asthma is a heterogeneous disease characterized by chronic

The two authors, Luigi La Via and Filippo Sanfilippo, equally airway inflammation and remodeling, responsible for vari-
contributed to the study.
able airflow obstruction, thickening of the airway wall and
* Luigi La Via increased mucus production. These pathophysiological fea-
[email protected] tures determine a wide range of symptoms such as wheez-
ing, dyspnea, chest tightness and cough, which may vary
1
Department of Anesthesiology and Intensive Care, AOU over time in onset, frequency and intensity [1]. Asthma
“Policlinico – San Marco”, 95123 Catania, Italy
prevalence ranges from 1 to 21% [2] in the adult popula-
2
School of Specialization in Anesthesia and Intensive Care, tion, with a significant health and economic burden [3], of
University of Catania, Catania, Italy
note, the incidence of asthma has increased by nearly 30%
3
School of Specialization in Anesthesia and Intensive Care, in the last 20 years [4]. Moreover, despite the availability
University “Magna Graecia”, Catanzaro, Italy
of effective and tailored pharmacological treatments [5–8]
4
Clinical Pharmacology Unit/Regional Pharmacovigilance targeting patients’ inflammatory and clinical phenotypes
Centre, University Hospital of Catania, Catania, Italy
[9, 10], satisfactory control of asthma symptoms is still an
5
Department of Pneumology, AOU “Policlinico – San unmet need [11] and a major challenge for clinicians [12].
Marco”, Catania, Italy

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1614 European Journal of Clinical Pharmacology (2022) 78:1613–1622

Suboptimal control of asthma may lead to frequent exac- Materials and methods
erbations and admission to the emergency department for
acute asthma attack. In particular, severe asthma exacerba- Search strategy and registration
tion (SAE) is a condition characterized by a progressive
increase in symptoms and with associated severe bronchos- We undertook a systematic web-based advanced literature
pasm requiring emergency room visits, monitoring and pos- search through the NHS Library Evidence tool on the effects
sibly hospitalization. of Ketamine in unresponsive asthma.
First-line management of SAEs includes inhaled short- The protocol of our systematic review was regularly
acting β-agonists, anticholinergics, and systemic corti- registered on PROSPERO (identified record number
costeroids, with the goals of relieving airflow obstruction CRD42021273466). We followed the approach suggested
and hypoxemia as quickly as possible; in refractory cases by the PRISMA statement for reporting systematic reviews
of SAE, intravenous magnesium sulfate and aminophyl- and meta-analyses [21] and a PRISMA checklist is provided
line can also be considered for the in-hospital management separately (Supplementary information 1).
[13]. Noninvasive ventilatory support is often required in Our core search was structured by combining the two
SAE cases [14] and nearly 10% of hospitalized SAE patients main terms of the topic: “ketamine” AND “asthma”. An
will also need intensive care unit admission. In the 2% most initial computerized search of PubMed was conducted from
severe cases, intubation and invasive mechanical ventilation inception until August ­12th, 2021 to identify the relevant
will also be required [15] with possible continuous infusion articles. We also performed a search on EMBASE limited to
of muscle relaxants. the findings from 2016 in order to retrieve the newest confer-
In addition to the conventional strategies for the treatment ence abstracts not yet published to allow a reasonable time
of SAE, another pharmacological option may be represented for the peer-review process. Two further searches were per-
by ketamine [16, 17]. Ketamine is a rapid onset drug with formed manually and independently by three authors, also
well-known sedative, analgesic and antiemetic effects [18]. exploring the list of references of the findings of the system-
The use of ketamine in severe asthma has been advocated atic search. Inclusion criteria were pre-specified according
for its sympathetic stimulation and the consequent relaxa- to the PICOS approach (Table 1).
tion of smooth muscles and bronchodilation [19]. Therefore, After an initial decision to include all type of studies
ketamine may improve lung compliance and reduce airways regardless of their methodological design, we preferred to
resistances when administered as a continuous infusion. select only prospective studies (randomized or not) in order
Moreover, it may increase bronchial secretions which may to focus on higher quality and level of evidence. Regarding
relieve mucus plugs [20]. Suggested dosages have been in the population, we accepted studies focusing on both adults
the range of 0.5 to 2 mg/kg/h [16]. Nonetheless, ketamine and pediatric patients where ketamine was used to treat
has several dose-dependent side effects, such as hyperten- refractory asthma and patients in the control group received
sion, tachycardia, increase in intracranial pressure and sed- placebo or other second-tier drugs for severe asthma. We
ative effects. Moreover, it can cause drooling, myoclonia, excluded retrospective studies, case series and case reports;
nystagmus, hallucinations and psychomotor agitation crises we also discarded experimental animal studies, book chap-
[18]. There are conflicting clinical reports on the value of ters, reviews, editorials and letters to the editor. Language
using ketamine in patients with SAE. Therefore, we per- restrictions were applied: we read the full manuscript only
formed a systematic search of the literature to explore the for articles published in English. For studies published in
role of ketamine in acute severe asthma unresponsive to con- other languages, we read the abstract and contacted the
ventional treatment.

Table 1  PICOS Criteria PICOS

Participants Adult and pediatric patients with severe asthma refractory to conventional therapy
Intervention Ketamine
Comparison Placebo or other pharmacological strategies
Outcome Improvement in oxygenation parameters; amelioration of clinical conditions;
reduction of escalation to invasive ventilation; facilitation in weaning from
mechanical ventilation; decrease in peak inspiratory pressures and increase in
lung compliance; evaluation of side effects
Studies included Randomized controlled trials; prospective studies for sensitivity analysis only

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European Journal of Clinical Pharmacology (2022) 78:1613–1622 1615

authors for further information, if necessary. Study selection Table 2 describes the characteristics of the included stud-
for determining the eligibility for inclusion in the systematic ies and the main results reported by the authors. With regard
review and data extraction was performed independently by to the study populations, a large heterogeneity was found
four reviewers. Discordances were resolved by two senior regarding the number of patients included and their distribu-
authors. Data were inserted in a password-protected Excel tion by gender and age. Regarding the inclusion criteria of
database. the single studies, three of them [24, 27, 29] did not clearly
specify the use of scores/criteria for patients’ selection. Of
Outcomes analysis the remaining four studies, one used criteria defined by the
authors [26], while the remaining three used known scores
We primarily compared the effects of ketamine as adjunctive for lung diseases:
therapy for severe refractory asthma on oxygenation and res-
piratory parameters (i.e. peak inspiratory pressures, airways – the Pediatric Respiratory Assessment Measure (PRAM)
resistance, lung compliance), and clinical status, need for score, which includes 5 parameters: suprasternal retrac-
invasive ventilation and effects on weaning from mechanical tion, contraction of the inspiratory scalene muscles, tho-
ventilation. As a secondary focus of our analysis, we evalu- racic excursion, wheezing, SpO2 [25];
ated the reported side effects in the patients treated with – the Pulmonary Index Score (PIS), which includes respira-
ketamine compared to the control group. We considered tory rates, wheezing, inspiratory/expiratory ratio, use of
the possibility to perform a quantitative assessment (meta- accessory muscles, SpO2 [23];
analysis) if at least three studies consistently reported the – the Clinical Asthma Score (CAS), which analyzes SpO2,
same outcome. wheezing, inspiratory breath sounds, use of accessory
muscles and neurological status [28].
GRADE of evidence
Regarding ketamine dosing, the included studies used dif-
Grade of evidence performed according to the recommen- ferent dosages of ketamine. In particular, most of the stud-
dations of the Grading of Recommendations Assessment, ies used an intravenous bolus dose of ketamine followed by
Development and Evaluation working group was preliminar- continuous infusion [25, 26, 28–30]. In these studies, the
ily considered only if meta-analysis was feasible. bolus ranged from 0.1 to 2.0 mg/kg, while the infusion was
used with a variable range from 0.5 to 2.0 mg/kg/h. Only
one study [24] used the ketamine bolus exclusively with
Results dosage ranging from 0.3 mg/kg to 0.5 mg/kg. Of the five
randomized studies with a control group, three compared
From our systematic search, 105 items were found on Pub- ketamine to placebo [23, 24, 27], while the remaining two
med and 71 on EMBASE (Fig. 1). We selected the poten- used fentanyl [26] (bolus 1 mcg/kg, followed by continuous
tially relevant articles and subsequently reviewed their infusion at 1 mcg/kg/h) or aminophylline [25] (slow bolus
full-text against our PICOS criteria. We initially included of 5 mg/kg over 20 min, followed by infusion 0.9 mg/kg/h
9 studies, but one was subsequently excluded because it for 3 h).
was a national survey conducted in Chile reporting the use The outcomes were variable in the different studies, gas
of pharmacological and non-pharmacological approaches, exchange ­(PaO2 and P­ aCO2) and respiratory mechanics indi-
outcomes and costs of the management of the asthma exac- ces (Ppeak, PEFR, ­FEV1) were mainly evaluated.
erbations in the pediatric population. Another study was Only three studies included complications as secondary
excluded as after evaluation of full text it was not focused on outcomes [25, 27, 28]. Tiwari et al. [25] observed hyperten-
asthma but included a heterogeneous population of mechani- sion in n = 2/24 patients in the ketamine group vs no one
cally ventilated patients admitted to intensive care who sub- in the aminophylline group (p = 0.49), and tachycardia was
sequently developed bronchospasm (defined as a thoracic noted in n = /24 and n = 21/24 in the ketamine and amino-
compliance below 35 mL/cmH2O) [22]. phylline groups, respectively (p = 0.49).
Therefore, we included a total of 7 studies, including
5 RCTs [23–27] with a population ranging from 44 to 92
enrolled patients, and 2 prospective studies of 10 and 11 Discussion
patients respectively (without the control group) [28, 29].
Of the seven included studies, four enrolled adults only [24, The purpose of our systematic review was to summarize the
26, 27, 29] and three focused on the pediatric population clinical evidence regarding the use of ketamine in patients
[23, 25, 28]. with severe asthma refractory to conventional medical

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1616 European Journal of Clinical Pharmacology (2022) 78:1613–1622

Fig. 1  Modified PRISMA 2009 flow diagram

treatment, selecting higher-quality studies (randomized and this patient population. Together with the reduced quality
prospective only). We found a paucity of data on the possible and quantity of data, we also noted a profound heterogene-
benefits and complications related to the use of ketamine in ity in the control group, where the treatment ranged from

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 Table 2  Summary of the included studies
First author, year, design N patients Inclusion criteria Ketamine dose(s) Outcomes studied by the Main results of each study
Median Age (range) Comparison dose authors

Esmailian M, N = 92 - - K: bolus 0.3 mg/kg (16.3%), PEFR before and 1 h after treat- - PEFR baseline K ­ 0.3: 346 ± 85, P:
2018; 48 years 0.4 mg/kg (15.2%), and 0.5 mg/ ment 336 ± 101 (p = 0.60)
RCT​ (34–62) kg (17.4%) - PEFR 1 h after K­ 0.3: 416 ± 76, P:
- Placebo 352 ± 101 (p = 0.001)
No side effects reported
Allen JY, 2005; N = 68 PIS > 8 - K: bolus 0.2 mg/kg + infusion PIS at 0, 30, 60, 90, and 120 min - PIS baseline K: 10 ± 1, P: 10 ± 1
RCT​ 6 years 0.5 mg/kg/h (2 h) No side effects reported (MD 0.2; 95%CI [− 0.5;0.8])
(2–10) - Placebo - PIS at 2 h K: 3 ± 2, P: 4 ± 1 (MD
0.4; 95%CI [− 0.4;1.3])
Tiwari A, 2016; N = 48 PRAM ≥ 5 after 2 h of standard - K: bolus 0.5 mg/kg ΔPRAM in the first 24 h, Hyper- ΔPRAM score in the first 24 h K:
RCT​ 48 months (16–144) therapy (20 min) + infusion 0.6 mg/ tension, Tachycardia 4.00 ± 1.25,
kg/h (3 h) A: 4.17 ± 1.68 (p = 0.70)
- Aminophylline: 5 mg/kg bolus No side effects reported
(20 min) + infusion 0.9 mg/
kg/h (3 h)
European Journal of Clinical Pharmacology (2022) 78:1613–1622

Nedel W, 2020; N = 45 - Adults intubated for acute - K: bolus 2 mg/kg + infusion Rsmax, ΔPEEPi, ΔCdyn at 3 h - Rsmax at 3 h: K: 0 ± 6, F: –3 ± 8,
RCT​ 65 years bronchospasm 2 mg/kg/h and 24 h after treatment p = 0.16
(51–79) -Rsmax ≥ 12 ­cmH2O/L/s - Fentanyl: bolus 1 mcg/ - Rsmax at 24 h: K: –3 ± 17, F:
kg + infusion of 1 mcg/kg/h –3 ± 14, p = 0.73
- ΔPEEPi at 3 h: K: 0 (95%CI
–1;1), F: –0.5 (–8;0), p = 0.77
- ΔPEEPi at 24 h: K: –1 (95%CI
–3;1), F: –0.5 (–5;2), p = 0.72
- ΔCdyn at 3 h: K: 0 (95%CI –2;2),
F: 0 (–2;3), p = 0.85
- ΔCdyn at 3 h: K: 1 (95%CI –6;3),
F: 0.5 (–11;3), p = 0.35
No side effects reported
Howton JC, 1996; N = 44 - - K: bolus 0.1 mg/kg + infusion Respiratory rate, Borg Score, - RR before vs after K: 29 ± 7 vs
RCT​ 33 years at 0.5 mg/kg/h Peak flow, F­ EV1 before and 24 ± 4; P: 30 ± 10 vs 24 ± 6
(26–40) - Placebo after treatment - Borg Score before vs after K:
6 ± 2 vs 3 ± 1; P: 6 ± 3 vs 3 ± 2
- Peak Flow before vs after K:
139 ± 53 vs 158 ± 48, P: 124 ± 49
vs 163 ± 91
- ­FEV1 before vs after K: 0.7 ± 0.3
vs 0.9 ± 0.3; P: 0.6 ± 0.4 vs
1.0 ± 0.6
- Adverse reactions K: 17.4%
(95%CI 5;39), P: 4.8% (12;24).
All the above results were not
significant

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 Table 2  (continued)
1618

First author, year, design N patients Inclusion criteria Ketamine dose(s) Outcomes studied by the Main results of each study
Median Age (range) Comparison dose authors

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Petrillo TM, 2001; N = 10 CAS > 12 - K: bolus 1 mg/kg + infusion CAS and PEFR before K bolus, - CAS baseline 14 (8–21). 10 min
Prospective 8 years 0.75 mg/kg/h (1 h) 10 min after K bolus, and 1 h after bolus 10 (4–12), 1 h after
(5–16) after infusion infusion 9 (4–12). Both results
p < 0.001
- PEFR baseline 16 ± 10 (0–46)
10 min after bolus 47 ± 14 (0–76).
1 h after infusion: 69 ± 8
(53–95). Both results p < 0.05
Hallucinations n = 2, hypertension
n = 1, diffuse skin flushing n = 1
Heshmati F, 2003; N = 11 - - K: bolus 1 mg/kg + infusion Ppeak, ­PaCO2, ­PaO2 before K - Ppeak baseline 75 ± 4. 15 min
Prospective 30 years 1 mg/kg/h (2 h) bolus, 15 min after bolus and after bolus 50 ± 5. 2 h after
(15–40) 2 h after infusion infusion 40 ± 5. Both results
p < 0.005
- ­PaCO2 baseline 71 ± 3. 15 min
after bolus 64 ± 4. 2 h after
infusion 45 ± 4. Both results
p < 0.005
- ­PaO2 baseline 63 ± 4. 15 min
after bolus 75 ± 4. 2 h after
infusion 92 ± 4. Both results
p < 0.005
No side effects reported

K ketamine, CAS clinical asthma score, Cdyn dynamic compliance, CI confidence interval, FEV1 forced expiratory volume in 1 s, MD mean difference, MV mechanical ventilation, PEEPi posi-
tive end expiratory pressure intrinsic, PEFR peak expiratory flow rate, Ppeak pressure peak, PIS pulmonary index score, PRAM pediatric respiratory assessment measure, RR, respiratory rate,
Rsmax airway resistance, RCT​randomized controlled trial
European Journal of Clinical Pharmacology (2022) 78:1613–1622
European Journal of Clinical Pharmacology (2022) 78:1613–1622 1619

placebo to other drugs such as fentanyl and aminophyl- decrease in Rsmax and a stability of Cdyn (albeit at severely
line. The ketamine dosages used were also largely different compromised values). In this sense, the decrease in respiratory
between studies. Furthermore, the outcomes evaluated by resistance over the course of 24 h in these patients was almost
the included studies, were profoundly variable. Therefore, identical between groups (ketamine and fentanyl), thus pos-
we could not conduct a quantitative analysis (meta-analysis) sibly attributable to other treatment strategies (b2-agonist and
and the evaluation remains quite subjective. steroid therapy) or eventually to similar effects of ketamine
Ketamine is a phencyclidine derivative with non-competitive and fentanyl. Interestingly, there was a progressive increase in
antagonist effects on N-methyl-D-aspartate (NMDA) receptors. PEEPi in both groups at 24 h. In this sense, it is possible that
However, it may clinically have numerous other effect sites, in the presence of low values of Cdyn, a reduction in Rsmax
both ion channels and receptors (i.e. L-type voltage-gated with an increase in minute-volume ventilation favored air trap-
Ca2 + channels, nicotinic and muscarinic acetylcholine recep- ping and lung hyperinflation. In one pediatric study, Tiwari
tors, voltage-sensitive Na + channels, μ and δ opioid receptors, et al. [25] compared ketamine to aminophylline and showed
etc.). This large number of target sites for ketamine may con- similar improvements in the PRAM score and gas exchange
tribute to the wide range of effects of the drug [31]. Regarding in both groups. Furthermore, the evaluation of side effects
the role of ketamine in asthma, bronchodilation is supposed to showed a similar (and high) incidence of tachycardia, while
be a combination of several targets: direct blockade of NMDA only two patients, both in the ketamine group, had developed
receptor-induced airway constriction, reduction of nitric oxide hypertension.
levels in pulmonary tissues (down-regulation of inducible nitric Of note, during the screening and the systematic research,
oxide synthetase activity), increase in synaptic catecholamine among the studies analyzed we also found a national mul-
levels (blockade of presynaptic re-uptake), inhibition of vagal ticenter survey conducted in Chile in children with asthma
outflow, direct smooth muscle relaxation by reduction of cal- exacerbation [36]. In this survey, all patients received sal-
cium influx (L-type calcium channels), reduction of inflam- butamol and 98% received systemic steroid administration.
mation with blunted macrophage recruitment and cytokine Regarding the additional rescue drug therapies to improve
production [32–35]. respiratory function, the most used medication was mag-
Despite this background, the results obtained from the nesium sulfate (6%) followed by aminophylline (0.8%) and
administration of ketamine in patients with severe refractory finally by an anecdotal use of ketamine (0.5%, n = 2/396).
asthma seem predominantly neutral or eventually negative. Although conducted in a single country and limited to the
Indeed, from the qualitative analysis of the included studies pediatric population, this survey confirms that ketamine
it would appear that ketamine did not offer particular clini- remains a drug rarely used in this setting. Notably, keta-
cal benefits. Therefore, our systematic review does not offer mine use is banned in some countries and undergoes special
significant support for the clinical use of ketamine with this legislation for its use in many others.
indication. In summary, from this overview of the included stud-
The only study showing some significant benefit from keta- ies, we noted an absence of any clear and relevant benefit
mine was conducted by Esmailian et al. [24] on 92 adults. This produced by the administration of ketamine in patients with
study was the largest one retrieved by our systematic review refractory asthma, and some signals towards side effects
and measured the Peak Expiratory Flow Rate (PEFR), evalu- related to its use.
ating the effects of increasing doses of Ketamine (0.3, 0.4 or However, we also found a randomized study published
0.5 mg/kg as a bolus only, without continuous infusion) as almost 30 years ago suggesting beneficial effects of keta-
compared to placebo. In this study, a significant improvement mine bolus (1 mg/kg) as compared to placebo in mechani-
in PEFR occurred for the 0.4 and 0.5 mg/kg bolus doses; how- cally ventilated adult patients admitted to intensive care and
ever, the authors did not perform any further measurements of developing bronchospasm. In particular, the authors found
respiratory function and mechanics. Furthermore, the authors improvement of gas exchange with increase in oxygenation
excluded patients reporting side effects from ketamine treat- and stable values of ­PaCO2 in the ketamine group while
ment [24]. In another study, Nedel et al. [26] compared the the oxygenation worsened and the P ­ aCO2 increased in the
effects of ketamine (2 mg/kg bolus and subsequent infusion placebo group [22]. Nonetheless, the benefits of ketamine
at 2 mg/kg/h) and fentanyl administration (bolus of 1 mcg/ in patients with refractory asthma seem unclear and its use
kg and continuous infusion of 1 mcg/kg/h). Main outcomes should be probably reserved for well-structured experimen-
were changes in respiratory mechanics (Airway Resistances – tal research setting with clear objectives and outcomes. On
Rsmax; intrinsic Positive End Expiratory Pressure – PEEPi; the other hand, performing a large randomized study may be
and dynamic compliance—Cdyn) at different time-points challenging as the number of patients presenting with acute
(pre-treatment, at 3 and 24 h). In both groups, there was a refractory asthma may not be very large.

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1620 European Journal of Clinical Pharmacology (2022) 78:1613–1622

Limitations need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

Our study presents several limitations. Firstly, the number of

included studies was low with a paucity of patients enrolled.
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P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H,
Abbreviations SAEs: Severe asthma exacerbations; RCT​: Rand-
Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT,
omized controlled trial; PRAM: Pediatric respiratory assessment
Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson
measure; PIS: Pulmonary index score; CAS: Clinical asthma score;
KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis
NMDA: N-methyl-D-aspartate; PEFR: Peak expiratory flow rate;
M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M,
Rsmax: Airway Resistances; PEEPi: Intrinsic Positive End Expira-
Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei
tory Pressure; Cdyn: Dynamic compliance.
G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos
A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD,
Supplementary Information The online version contains supplemen- Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00228-0​ 22-0​ 3374-3. H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ,
Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT,
Author contribution Conception and design: LLV, GC, FS; Collec- Ferrari A, Ferri CP, Fèvre EM, Finucane MM, Flaxman S, Flood
tion and assembly of data: VD, MF, GC, CC; Data analysis and inter- L, Foreman K, Forouzanfar MH, Fowkes FG, Franklin R, Fransen
pretation: FS, LLV, MA, SB; Manuscript writing: All authors; Final M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA,
approval of manuscript: All authors. Garcia B, Gaspari F, Gillum RF, Gmel G, Gosselin R, Grainger R,
Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H,
Funding Open access funding provided by Università degli Studi di Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller
Catania within the CRUI-CARE Agreement. R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ,
Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis
D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan
Data availability On request to the corresponding author.
G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH,
Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R,
Declarations Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh
J, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W,
Conflict of interest The authors declare no competing interests. Loane M, Ohno SL, Lyons R, Ma J, Mabweijano J, MacIntyre
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March L, Margolis DJ, Marks GB, Marks R, Matsumori A,
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