Received: 5 November 2021 | Revised: 29 November 2021 | Accepted: 1 December 2021
DOI: 10.1111/pan.14354
E D U C AT I O N A L R E V I E W
Aerosolized drug delivery in awake and anesthetized children
to treat bronchospasm
Natalie Anderson1,2 | Sarah Clarke3 | Britta S. von Ungern-Sternberg1,4,5
1
Perioperative Medicine, Telethon Kids
Institute, Nedlands, WA, Australia Summary
2
School of Population Health, Curtin Bronchospasm is a common respiratory adverse event in pediatric anesthesia. First-
University, Bentley, WA, Australia
3
line treatment commonly includes inhaled salbutamol. This review focuses on the cur-
Emergency Department, Perth Children’s
Hospital, Perth, WA, Australia rent best practice to deliver aerosolized medications to awake as well as anesthetized
4
Department of Anaesthesia and Pain pediatric patients and discusses the advantages and disadvantages of various admin-
Management, Perth Children’s Hospital,
istration techniques. Additionally, we detail the differences between various airway
Perth, WA, Australia
5
Division of Emergency Medicine, devices used in anesthesia. We highlight the unmet need for innovation of orally in-
Anaesthesia and Pain Medicine, Medical haled drug products to deliver aerosolized medications during pediatric respiratory
School, The University of Western
Australia, Perth, WA, Australia critical events such as bronchospasm. It is therefore important that clinicians remain
up to date with the best clinical practice for aerosolized drug delivery in order to pre-
Correspondence
Britta S. von Ungern-Sternberg, vent and efficiently treat pediatric patients experiencing life-threatening respiratory
Department of Anaesthesia and Pain emergencies.
Medicine, Perth Children’s Hospital, 15
Hospital Avenue, 6009 Nedlands, WA,
KEYWORDS
Australia.
Email: Britta.regli-vonungern@health. aerosol, anesthesia, nebulizer, pediatric, perioperative adverse events, salbutamol
wa.gov.au
Funding information
BvUS is partly funded by the Stan Perron
Charitable Foundation.
Editor: Thomas Engelhardt
1 | I NTRO D U C TI O N administration 1) drug-
device combination products (medicinal
products—primary mode of action is attributable to the drug compo-
Bronchospasm is a common respiratory adverse event in pediatric nent), for example, pressurized metered dose inhalers (pMDI) and 2)
anesthesia. First-line treatment for bronchospasm is usually inhaled device-only products, for example, spacer actuators (in-line spacers),
salbutamol (albuterol), a short-acting beta-agonist (SABA), or adren- universal adaptors (mini-spacers), spacers, or nebulizers.1,2 Dry pow-
aline, a non-selective adrenergic agonist—to reduce airway constric- der inhalers are not typically used to administer emergency med-
tion and/or edema. The aim of this review is to examine current best icines (since they commonly require a significant inspiratory flow)
practice for the delivery of orally inhaled drug products to treat and are therefore outside the scope of this review.
bronchospasm in awake and anesthetized children, and to identify Drug-device combination products are designed to be tested for
clinical practice aimed at prevention of perioperative bronchospasm. safety together with a specific drug prior to going onto the market.
Closing the gap between aerosol delivery science and clinical prac- In contrast, device-only products are intended to either replace the
tice is essential to minimize morbidity and mortality by facilitating actuator/aerosol generator of an already existing drug-device prod-
a safe recovery and by identifying potential areas for technological uct (eg, in-line spacers, mini-spacers) or to be used with an already
improvements. existing drug product (eg, nebulizers, spacers). Clinicians have to
Orally inhaled drug products, such as those delivering salbu- keep in mind that device-only products are not required to conform
tamol or adrenaline, can be divided into two categories during drug with drug-device combination product legislation and that there are
156 | © 2021 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/pan Pediatric Anesthesia. 2022;32:156–166.
, |
14609592, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pan.14354 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [13/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ANDERSON et al. 157
no drug-device combination products approved for use in a venti- development which means few new products reach the market. 22
lation line to date. 2-4 Additionally, aerosol delivery devices are de- Furthermore, orally inhaled drug products are considered a “complex
signed for adults not children and thus "off-label” use, in this sense, therapeutic,” and are thus more difficult to produce. 22 Considering
5-7
is common. Therefore, any clinical adaptations for pediatrics this unmet need for innovation in orally inhaled drug products, it
deemed necessary are tested for evidence base in hindsight—if at is therefore important that clinicians remain reliant on the most up
7,8
all—to allow the proper translation into clinical practice. to date, best clinical practice for aerosolized drug delivery in order
In awake patients, salbutamol administration via a pMDI—a drug- to both prevent and efficiently treat pediatric patients experiencing
device combination product—with an accessory spacer device, is the life-threatening respiratory emergencies.
gold standard because they are both cheap, portable, and consid-
ered easy to use.9 A pMDI, while seemingly easy to use, is in fact
difficult to use correctly, as demonstrated by both patients and cli- 2 | S E A RC H M E TH O D
nicians, and has not improved over time.10,11 Furthermore, spacer
devices are a post-market add-on and need to be carefully consid- Search period: 2011–2021.
ered, since different spacers used with different drugs will deliver Data bases: Pubmed, UpToDate.
aerosol differently and should not be considered interchangeable.12 Search Terms: bronchospasm, anesthesia, intraoperative bron-
Correct usage of a pMDI with a spacer involves a series of steps, chospasm, pediatric croup, post-extubation stridor, intraoperative
as per the manufacturer instructions, which includes 1) “priming” bronchospasm pediatric, perioperative bronchospasm pediatric,
the pMDI device by actuating two puffs into the air before use, in nebulizer therapy, croup, medical aerosol in acute and critical care.
order to ensure no vapor or air bubbles are present in the metering Reference lists from identified articles were also included.
chamber (that can form during storage and temperature cycling), 2)
shaking the device well (for ~5 s) before and between doses, 3) hold-
ing the device upright and inhaling at the same time as actuating the 3 | E PI D E M I O LO G Y
device, and 4) waiting for ~30 s between dosing.13 Shaking between
use may not be required with newer formulations that are in a hy- Acute asthma is the fourth most common reason for pediatric pres-
drofluoroalkane propellant, although this is yet to be confirmed.11,14 entations to the emergency department. 23 Most asthma hospitaliza-
Even when a salbutamol pMDI is used with a spacer and facemask tions are in children and the hospitalization rate for children (aged
correctly—according to the manufacturer instructions—it will deliver 0–14) is 363 per 100 000 population with a death rate of 1.3 in
between approximately 2–7.5% of the labeled claim dose to awake 100 000. 24
young children (<5 years) in a non-acute setting, which is similar to In the perioperative period, in general, 1 in 7 children experi-
15,16
that delivered by a nebulizer, but in a shorter time. The dose ad- ence a respiratory adverse event (eg, laryngospasm, bronchospasm,
ministered will be further reduced if the device is not used as per the desaturation), with this rate further increasing in children with risk
manufacturer instructions, or if there is a facemask leak.15 factors (eg, recent upper respiratory tract infection, nocturnal dry
In anesthetized and/or ventilated children, the aerosolized cough). 25,26 Approximately one in a hundred children undergoing
drug is often administered in the inspiratory limb of the ventilator surgery will experience bronchospasm. 25,26
circuit with a device-only product as there are currently no drug-
device combination products on the market designed for this use.17
Similarly, there is currently only one drug-device product used to 4 | TR E ATM E NT
treat respiratory emergencies—the pMDI; however, even the pMDI
is used with an untested-prior-to-market add-on device—the spacer. Treatment for bronchospasm often involves the delivery of aer-
In fact, only two conceptually new drug-device products have been osolized medication by a medicinal product (a drug-d evice com-
introduced since the pMDI in the 1950s—the dry powder inhaler bination product) or a medical device (a device-
only product)
and the soft-mist inhaler (or liquid metered dose inhaler), but neither that administers medicines for inhalation. The combination of
are used in emergency medicine and nebulizers are a device-only a drug with a device has an essential impact on the safety and
product.1–3,18 There have been many upgrades to the existing pMDI efficacy of the medicine, especially when it is intended to treat
since its introduction, including 1) the switch to “F gases” as the pro- a life-threatening condition such as bronchospasm. 27 Only the
pellant instead of chlorofluorocarbons to address the ozone hole manufacturer intended combination of drug-d evice product are
as a result of the Montreal Protocol in 1987, and resultant changes properly tested for safety and efficacy with the medication they
to formulations,14,19 2) introduction of breath-actuated inhalers in deliver before they go to market and thus will produce aerosolized
the 1990s, 20 and 3) the addition of dose counters and combination- medication: (1) without failure of the delivery mechanism, and
drugs to address the longstanding issue of severe asthma exacer- (2) of an adequate, respirable size; both are essential to ensure
bations associated with poor adherence to treatment by patients drug will reach the lungs and provide relief of symptoms. 27 For
21
with mild asthma. The reason for the lack of new products may example, the European Medicines Agency specifies that, before
well be due to the 70% failure rate for orally inhaled drug product the product goes to market, the manufacturer must confirm that
DOI: 10.1111/pan.14354
E D U C AT I O N A L R E V I E W
Aerosolized drug delivery in awake and anesthetized children
to treat bronchospasm
Natalie Anderson1,2 | Sarah Clarke3 | Britta S. von Ungern-Sternberg1,4,5
1
Perioperative Medicine, Telethon Kids
Institute, Nedlands, WA, Australia Summary
2
School of Population Health, Curtin Bronchospasm is a common respiratory adverse event in pediatric anesthesia. First-
University, Bentley, WA, Australia
3
line treatment commonly includes inhaled salbutamol. This review focuses on the cur-
Emergency Department, Perth Children’s
Hospital, Perth, WA, Australia rent best practice to deliver aerosolized medications to awake as well as anesthetized
4
Department of Anaesthesia and Pain pediatric patients and discusses the advantages and disadvantages of various admin-
Management, Perth Children’s Hospital,
istration techniques. Additionally, we detail the differences between various airway
Perth, WA, Australia
5
Division of Emergency Medicine, devices used in anesthesia. We highlight the unmet need for innovation of orally in-
Anaesthesia and Pain Medicine, Medical haled drug products to deliver aerosolized medications during pediatric respiratory
School, The University of Western
Australia, Perth, WA, Australia critical events such as bronchospasm. It is therefore important that clinicians remain
up to date with the best clinical practice for aerosolized drug delivery in order to pre-
Correspondence
Britta S. von Ungern-Sternberg, vent and efficiently treat pediatric patients experiencing life-threatening respiratory
Department of Anaesthesia and Pain emergencies.
Medicine, Perth Children’s Hospital, 15
Hospital Avenue, 6009 Nedlands, WA,
KEYWORDS
Australia.
Email: Britta.regli-vonungern@health. aerosol, anesthesia, nebulizer, pediatric, perioperative adverse events, salbutamol
wa.gov.au
Funding information
BvUS is partly funded by the Stan Perron
Charitable Foundation.
Editor: Thomas Engelhardt
1 | I NTRO D U C TI O N administration 1) drug-
device combination products (medicinal
products—primary mode of action is attributable to the drug compo-
Bronchospasm is a common respiratory adverse event in pediatric nent), for example, pressurized metered dose inhalers (pMDI) and 2)
anesthesia. First-line treatment for bronchospasm is usually inhaled device-only products, for example, spacer actuators (in-line spacers),
salbutamol (albuterol), a short-acting beta-agonist (SABA), or adren- universal adaptors (mini-spacers), spacers, or nebulizers.1,2 Dry pow-
aline, a non-selective adrenergic agonist—to reduce airway constric- der inhalers are not typically used to administer emergency med-
tion and/or edema. The aim of this review is to examine current best icines (since they commonly require a significant inspiratory flow)
practice for the delivery of orally inhaled drug products to treat and are therefore outside the scope of this review.
bronchospasm in awake and anesthetized children, and to identify Drug-device combination products are designed to be tested for
clinical practice aimed at prevention of perioperative bronchospasm. safety together with a specific drug prior to going onto the market.
Closing the gap between aerosol delivery science and clinical prac- In contrast, device-only products are intended to either replace the
tice is essential to minimize morbidity and mortality by facilitating actuator/aerosol generator of an already existing drug-device prod-
a safe recovery and by identifying potential areas for technological uct (eg, in-line spacers, mini-spacers) or to be used with an already
improvements. existing drug product (eg, nebulizers, spacers). Clinicians have to
Orally inhaled drug products, such as those delivering salbu- keep in mind that device-only products are not required to conform
tamol or adrenaline, can be divided into two categories during drug with drug-device combination product legislation and that there are
156 | © 2021 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/pan Pediatric Anesthesia. 2022;32:156–166.
, |
14609592, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pan.14354 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [13/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ANDERSON et al. 157
no drug-device combination products approved for use in a venti- development which means few new products reach the market. 22
lation line to date. 2-4 Additionally, aerosol delivery devices are de- Furthermore, orally inhaled drug products are considered a “complex
signed for adults not children and thus "off-label” use, in this sense, therapeutic,” and are thus more difficult to produce. 22 Considering
5-7
is common. Therefore, any clinical adaptations for pediatrics this unmet need for innovation in orally inhaled drug products, it
deemed necessary are tested for evidence base in hindsight—if at is therefore important that clinicians remain reliant on the most up
7,8
all—to allow the proper translation into clinical practice. to date, best clinical practice for aerosolized drug delivery in order
In awake patients, salbutamol administration via a pMDI—a drug- to both prevent and efficiently treat pediatric patients experiencing
device combination product—with an accessory spacer device, is the life-threatening respiratory emergencies.
gold standard because they are both cheap, portable, and consid-
ered easy to use.9 A pMDI, while seemingly easy to use, is in fact
difficult to use correctly, as demonstrated by both patients and cli- 2 | S E A RC H M E TH O D
nicians, and has not improved over time.10,11 Furthermore, spacer
devices are a post-market add-on and need to be carefully consid- Search period: 2011–2021.
ered, since different spacers used with different drugs will deliver Data bases: Pubmed, UpToDate.
aerosol differently and should not be considered interchangeable.12 Search Terms: bronchospasm, anesthesia, intraoperative bron-
Correct usage of a pMDI with a spacer involves a series of steps, chospasm, pediatric croup, post-extubation stridor, intraoperative
as per the manufacturer instructions, which includes 1) “priming” bronchospasm pediatric, perioperative bronchospasm pediatric,
the pMDI device by actuating two puffs into the air before use, in nebulizer therapy, croup, medical aerosol in acute and critical care.
order to ensure no vapor or air bubbles are present in the metering Reference lists from identified articles were also included.
chamber (that can form during storage and temperature cycling), 2)
shaking the device well (for ~5 s) before and between doses, 3) hold-
ing the device upright and inhaling at the same time as actuating the 3 | E PI D E M I O LO G Y
device, and 4) waiting for ~30 s between dosing.13 Shaking between
use may not be required with newer formulations that are in a hy- Acute asthma is the fourth most common reason for pediatric pres-
drofluoroalkane propellant, although this is yet to be confirmed.11,14 entations to the emergency department. 23 Most asthma hospitaliza-
Even when a salbutamol pMDI is used with a spacer and facemask tions are in children and the hospitalization rate for children (aged
correctly—according to the manufacturer instructions—it will deliver 0–14) is 363 per 100 000 population with a death rate of 1.3 in
between approximately 2–7.5% of the labeled claim dose to awake 100 000. 24
young children (<5 years) in a non-acute setting, which is similar to In the perioperative period, in general, 1 in 7 children experi-
15,16
that delivered by a nebulizer, but in a shorter time. The dose ad- ence a respiratory adverse event (eg, laryngospasm, bronchospasm,
ministered will be further reduced if the device is not used as per the desaturation), with this rate further increasing in children with risk
manufacturer instructions, or if there is a facemask leak.15 factors (eg, recent upper respiratory tract infection, nocturnal dry
In anesthetized and/or ventilated children, the aerosolized cough). 25,26 Approximately one in a hundred children undergoing
drug is often administered in the inspiratory limb of the ventilator surgery will experience bronchospasm. 25,26
circuit with a device-only product as there are currently no drug-
device combination products on the market designed for this use.17
Similarly, there is currently only one drug-device product used to 4 | TR E ATM E NT
treat respiratory emergencies—the pMDI; however, even the pMDI
is used with an untested-prior-to-market add-on device—the spacer. Treatment for bronchospasm often involves the delivery of aer-
In fact, only two conceptually new drug-device products have been osolized medication by a medicinal product (a drug-d evice com-
introduced since the pMDI in the 1950s—the dry powder inhaler bination product) or a medical device (a device-
only product)
and the soft-mist inhaler (or liquid metered dose inhaler), but neither that administers medicines for inhalation. The combination of
are used in emergency medicine and nebulizers are a device-only a drug with a device has an essential impact on the safety and
product.1–3,18 There have been many upgrades to the existing pMDI efficacy of the medicine, especially when it is intended to treat
since its introduction, including 1) the switch to “F gases” as the pro- a life-threatening condition such as bronchospasm. 27 Only the
pellant instead of chlorofluorocarbons to address the ozone hole manufacturer intended combination of drug-d evice product are
as a result of the Montreal Protocol in 1987, and resultant changes properly tested for safety and efficacy with the medication they
to formulations,14,19 2) introduction of breath-actuated inhalers in deliver before they go to market and thus will produce aerosolized
the 1990s, 20 and 3) the addition of dose counters and combination- medication: (1) without failure of the delivery mechanism, and
drugs to address the longstanding issue of severe asthma exacer- (2) of an adequate, respirable size; both are essential to ensure
bations associated with poor adherence to treatment by patients drug will reach the lungs and provide relief of symptoms. 27 For
21
with mild asthma. The reason for the lack of new products may example, the European Medicines Agency specifies that, before
well be due to the 70% failure rate for orally inhaled drug product the product goes to market, the manufacturer must confirm that
