Inhaler

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Inhaler
AsthmaInhaler.jpg
Metered-dose inhaler (MDI)
Specialty pulmonology

An inhaler (puffer, asthma pump or allergy spray) is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with asthma and chronic obstructive pulmonary disease (COPD) being among the most notable. [1]

Contents

Some of the common types of inhalers include metered-dose inhalers, dry powder inhalers, soft mist inhalers, and nebulizers. Each device has advantages and disadvantages and can be selected based on individually specific patient needs, as well as age, pathological conditions, coordination, and lung function. [2] Proper education on inhaler use is important to ensure that inhaled medication creates its proper effects in the lungs. [3] Using a spacer can ensure that more medicine reaches the lungs, thus providing the most optimal treatment.

Medical uses

Inhalers are designed to deliver medication directly to the lungs through a person's own breathing. This may benefit a patient by providing medicines directly to areas of disease, allowing medication to take a greater effect on its intended target, and limit side effects of medications when administered locally. [1] Inhalers are used in a variety of different medical conditions with diseases of the lungs and respiratory system being among the most common. Individuals with these diseases/conditions need medications designed to decrease airway inflammation and obstruction to allow for easier and comfortable breathing. [4] Antibiotic medications have even been developed for inhalers to allow for direct delivery to areas of infection within the lungs. [5] Two of the most common conditions that warrant inhaler therapy are asthma and chronic obstructive pulmonary disease. [4] [6]

Asthma

Asthma is a condition of intermittent airway obstruction due to inflammatory processes in the lungs. Inhaled medications are used to calm down the inflammation present in the lungs and allow for relief of the airway obstruction. Common inhaled medications used for treatment of asthma include long term inhalational steroidal anti-inflammatory drugs (most commonly inhaled corticosteroids, also called ICS) and fast-relieving bronchodilators such as salbutamol (known commonly as "Ventolin") and salmeterol. These medications allow for patients to have relief of airway obstruction symptoms and reduced inflammation. [4] If some people are unable to use inhalers, non-steroidal anti-inflammatory drugs (NSAIDs) may be used, but with caution since they may cause immunological hypersensitivity to NSAIDs, resulting in respiratory-related symptoms such as bronchospasms, acute asthma exacerbation, and severe asthma morbidity. [7] [8]

Chronic obstructive pulmonary disease (COPD)

COPD is an obstructive lung disease due to long-term damage to the airways of the lungs. The long-term damage leads to the inability of the airways to open properly, causing airway obstruction. Inhaled medications allow patients to see improvement in symptoms and better function of daily living. Some commonly used inhaled medications in patient's with COPD are ipratroprium, salmeterol, and corticosteroids. [6] Inhalers that combine two or three different medications including inhaled corticosteroids, long-active muscarinic medications (LAMA) and long acting beta2 agonists (LABA) for treating COPD may be associated with improvements in some quality of life variables and small improvements in lung function and respiratory symptoms, however, may also be associated with an increase in the risk of pneumonia. [9]

Types of inhalers

Meter-dosed inhaler (MDI)

The most common type of inhaler is the pressurifzed metered-dose inhaler (MDI) which is made up of 3 standard components- a metal canister, plastic actuator, and a metering valve. The medication is typically stored in solution in a pressurized canister that contains a propellant or suspension. The MDI canister is attached to a plastic, hand-operated actuator. On activation, the metered-dose inhaler releases a fixed dose of medication in aerosol form through the actuator and into a patient's lungs. [10] These devices require significant coordination as a person must discharge the medication at or near the same time that they inhale in order for the medication to be effective. [11]

Dry powder inhaler (DPI)

Different types of dry powder inhalers Dry powder inhalers.jpg
Different types of dry powder inhalers

Dry powder inhalers release a metered or device-measured dose of powdered medication that is inhaled through a DPI device. This device usually contains a chamber in which the powdered medication is deposited prior to each dosage. [3] The powder can then be inhaled with a quick breath. [1] This allows for medication to be delivered to the lungs without the need for use of propellant/suspension. [11]

Soft mist inhaler (SMI)

Soft mist inhalers release a light mist containing medication without the need for a propellant/suspension. Upon pressing a button, the inhaler creates a mist of medication, allowing for inhalation into the lungs. SMIs suspend inhaled medications for roughly 1.2 seconds, which is longer than the average MDI inhaler suspension time period. This requires less coordination when using and may be helpful for young patients or patients that find the MDI inhalers difficult to use. [11]

Nebulizer

Nebulizer with face mask Nebulizer Mask (Child).png
Nebulizer with face mask

Nebulizers are designed to deliver medications over an extended period of time over multiple breaths through a mouthpiece or face mask. They generate a continuous mist with aerosolized medication, allowing a patient to breathe normally and receive medications. [11] They are commonly used in infants and toddlers requiring inhaled medications or in patients in the hospital who require inhaled medications. [2]

Smart inhaler

The smart-inhaler is an inhaler that will automatically update an app with information that includes the time of day, air quality, and how many times it has been used through sensor technology on the device. [12] The first smart-inhaler was approved in 2019 by the FDA, its purpose is to track patient use of the device and some other circumstantial factors that could affect the effectiveness of the dosage. [12] This information is sent via Bluetooth to a mobile device app, and is later shared with their physician to determine what kind of things can trigger issues with asthma and other problems. [12] This technology presents a great way to cut down on medical costs associated with asthma and also help patients better manage their condition with fewer emergencies.

The Teva ProAir Digihaler was the first FDA approved smart inhaler. [13] It shows how effective the device is at aiding patients in using the proper dose amount for their asthma. In a study published by the European Respiratory Journal, the ProAir Digihaler accurately identified when patients were using their inhalers and whether they were effectively administering the dose in a 370 patient trial with the device. [13] This study further gives an overview on the technology regarding applications and devices that help aid in the tracking and medication management for asthma and other lung conditions. Another study showed that smart inhalers accurately recorded all doses administered by patients with their technology, which signifies their importance in providing accurate dosage information to patients and their physicians. [14]

Propellants

In 2009, the FDA banned the use of inhalers that use chlorofluorocarbons (CFC) as propellants. In their place, inhalers now use hydrofluoroalkane (HFA). HFA is not environmentally inert as it is a greenhouse gas but it does not affect the ozone layer. [15] While some people with asthma and advocacy groups contend that HFA inhalers are not as effective, [16] published clinical studies indicate CFC and HFA inhalers are equally effective in controlling asthma. [17]

While the impact of CFCs from inhalers on the ozone layer had been minuscule (dwarfed by industrial processes using CFCs), the FDA in its interpretation of the Montreal Protocol mandated the switch in propellants. [15] Patients expressed concern about the high price of the HFA inhalers as there were initially no generic versions, whereas generic CFC inhalers had been available. [16]

Proper use

It is important to use proper techniques when administering medications through inhalers.

Proper use of inhalers often involves initial deep breathing (which involves mostly the diaphragm's movements), and then rapid breathing [18] (which involves most of the muscles of respiration, such as external and internal intercostal muscles [19] ) during intake of one or more puffs from the inhalers.

Improper use of inhalers is very common, can lead to distribution of the medicine into the mouth or throat where it cannot create its desired effect and may cause harm. [1] [20] [21] Education on the correct use of inhalers for delivery of medications is a commonly cited topic in medical studies and a great deal of thought has been put into how best to help people learn to use their inhalers effectively. [22] [3] Below is a description of proper inhaler technique for each different type of inhaler as well as a helpful video explaining what the text states.

Using an inhaler

Meter-dosed inhalers

1. The mouthpiece is removed and the inhaler is shaken for 5–10 seconds.

2. The inhaler is gripped with mouthpiece on the bottom and canister on top. A finger is placed on the canister to allow for delivery of medicine.

3. Deep inhalation is done until no more air can be taken into the lungs.

4. Deep exhalation is done until most of the air is out of the lungs.

5. Once deep exhalation is done, mouth is placed over mouthpiece.

6. As the next deep inhalation begins, the canister is pressed down to release the medicine into the lungs.

5. Slow deep breathing is continued and breath is held for 5–10 seconds, keeping the medicine in the lungs for a longer time period and preventing escape of aerosolized form of the medicine.

6. Complete exhalation is done again. If multiple puffs of the medicine have to be taken, steps 1–5 are repeated after waiting for 15–30 seconds.

7. Mouthpiece is replaced. [1]

With spacer

Spacer is placed at the mouthpiece of a meter-dosed inhaler while keeping mouth at the end of the spacer. Deep breathing is done to be ready for the delivery of the medicine to the lungs, and then the canister is pressed down. This minimizes need for coordination of breathing with inhaler activation. [1]

Dry powder inhalers

1. Inhaler medication chamber is prepared (this will be different based on the type of inhaler but will involve preparing and opening the chamber with the medication)

2. The inhaler is held with the chamber pointing towards the patient and complete exhalation is done with their head turned away from the inhaler.

3. Mouth is placed over the chamber and a quick, deep breath is taken allowing medication to dispense in the lungs.

4. Breath is held for 5–10 seconds and then slow exhalation is done.

5. After waiting for a few minutes, steps 1-4 are repeated if another dose is needed. [1]

Soft mist inhalers

1. The inhaler is primed by loading the cartridge and discharging the inhaler until a fine mist is visible (more explanation in the video).

2. Once complete exhalation is done, mouth is placed around the mouthpiece while leaving space for the small holes on the side of the mouthpiece.

3. Slow inhalation is done while simultaneously pressing the button to release the medication.

4. Breath is held for 5–10 seconds.

5. Slow exhalation is done and steps 1-4 are repeated if another dose of medication is required after waiting for a few minutes.

If inhaler is used everyday, the inhaler usually has to be primed the first time using a new cartridge, but it may need to be primed again if it has not been used in multiple days. [1]

After use

If using inhaled corticosteroids, one should wash the mouth out directly after use of an inhaler. This helps to prevent mouth infections that can occur due to immunosuppressant effects of corticosteroids. [1]

Nebulizer

1. Mouth is placed over mouthpiece or face mask is placed over nose and mouth

2. The nebulizer machine is turned on.

3. Normal breathing is done for 10-20 min (or time allotted for treatment).

4. Machine is turned off and face mask/mouthpiece remove is removed. [1]

Price and availability

In the United States, pharmaceutical manufacturers use legal and regulatory strategies to keep inhaler prices artificially high. There has been little innovation in inhaler technology for decades — the most recent drug to be approved by the FDA for treating asthma or COPD via a novel target of action was Ipratropium bromide in 1986. Since then, manufacturers have used small changes to drug delivery mechanisms, or have switched active ingredients from one inhaler device to another (a strategy known as a "device hop") to keep patents active. This has the effect of limiting competition, keeping inhalers expensive. [23] Because of high prices, patients sometimes skip doses or give up using their inhalers.

History

Penetro brand inhaler from mid 20th century Mexico, part of the permanent collection of the Museo del Objeto del Objeto PenetroInhalador.JPG
Penetro brand inhaler from mid 20th century Mexico, part of the permanent collection of the Museo del Objeto del Objeto
Inhaler designed by John Mudge in 1778 Mudge inhaler.jpg
Inhaler designed by John Mudge in 1778

The idea of directly delivering medication into the lungs was based on ancient traditional cures that involved the use of aromatic and medicinal vapors. These did not involve any special devices beyond the apparatus used for burning or heating to produce fumes. Early inhalation devices included one devised by John Mudge in 1778. It had a pewter mug with a hole allowing attachment of a flexible tube. Mudge used it for the treatment of coughs using opium. These devices evolved with modifications by Wolfe, Mackenzie (1872) and better mouth attachments such as by Beigel in 1866. Many of these early inhalers needed heat to vaporize the active chemical ingredient. The benefits of forced expiration and inspiration to treat asthma were noted by J. S. Monell in 1865. Chemicals used in inhalers included ammonia, chlorine, iodine, tar, balsams, turpentine camphor and numerous others in combinations. [24] Julius Mount Bleyer used a variation in 1890 in New York. [25]

Mouthpiece for an inhaler designed by Dr Beigel (1867) Beigel mouthpiece.jpg
Mouthpiece for an inhaler designed by Dr Beigel (1867)

In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia. [26] The Analgizer consisted of a polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick of polypropylene felt which held 15  milliliters of methoxyflurane.

Because of the simplicity of the Analgizer and the pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly amnesic to the sense of pain; the device could be refilled if necessary. [27]

The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with bone fractures and joint dislocations, [27] and for dressing changes on burn patients. [28] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores. [27] All vital signs remain normal in obstetric patients, newborns, and injured patients. [27] The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today. [29] [30] [31] [32] The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler. [33] [34] [35] [36] [37] [38]

See also

Related Research Articles

A bronchodilator or broncholytic is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be originating naturally within the body, or they may be medications administered for the treatment of breathing difficulties, usually in the form of inhalers. They are most useful in obstructive lung diseases, of which asthma and chronic obstructive pulmonary disease are the most common conditions. Although this remains somewhat controversial, they might be useful in bronchiolitis and bronchiectasis. They are often prescribed but of unproven significance in restrictive lung diseases.

<span class="mw-page-title-main">Inhaler spacer</span>

A spacer is a device used to increase the ease of administering aerosolized medication from a metered-dose inhaler (MDI). It adds space in the form of a tube or "chamber" between the mouth and canister of medication. Most spacers have a one-way valve that allows the person to inhale the medication while inhaling and exhaling normally; these are often referred to as valved holding chambers (VHC).

<span class="mw-page-title-main">Salbutamol</span> Short-acting bronchodilator used for acute asthma

Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist that causes relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks and exercise-induced bronchoconstriction, as well as chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution. Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.

<span class="mw-page-title-main">Nebulizer</span> Drug delivery device

In medicine, a nebulizer or nebuliser is a drug delivery device used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of asthma, cystic fibrosis, COPD and other respiratory diseases or disorders. They use oxygen, compressed air or ultrasonic power to break up solutions and suspensions into small aerosol droplets that are inhaled from the mouthpiece of the device. An aerosol is a mixture of gas and solid or liquid particles.

<span class="mw-page-title-main">Ipratropium bromide</span> Type of anticholinergic

Ipratropium bromide, sold under the trade name Atrovent among others, is a type of anticholinergic medication which is applied by different routes: inhaler, nebulizer, or nasal spray, for different reasons.

<span class="mw-page-title-main">Salmeterol</span> Chemical compound

Salmeterol is a long-acting β2 adrenergic receptor agonist (LABA) used in the maintenance and prevention of asthma symptoms and maintenance of chronic obstructive pulmonary disease (COPD) symptoms. Symptoms of bronchospasm include shortness of breath, wheezing, coughing and chest tightness. It is also used to prevent breathing difficulties during exercise.

<span class="mw-page-title-main">Formoterol</span> Bronchiodilator Drug

Formoterol, also known as eformoterol, is a long-acting β2 agonist (LABA) used as a bronchodilator in the management of asthma and chronic obstructive pulmonary disease (COPD). Formoterol has an extended duration of action compared to short-acting β2 agonists such as salbutamol (albuterol), which are effective for 4 h to 6 h. Formoterol has a relatively rapid onset of action compared to other LABAs, and is effective within 2-3 minutes. The 2022 Global Initiative for Asthma report recommends a combination formoterol/inhaled corticosteroid inhaler as both a preventer and reliever treatment for asthma in adults. In children, a short-acting β2 adrenergic agonist is still recommended.

Beta<sub>2</sub>-adrenergic agonist Compounds that bind to and activate adrenergic beta-2 receptors

Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β2 adrenergic agonists' effects on smooth muscle cause dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders. Bronchodilators are considered an important treatment regime for chronic obstructive pulmonary disease (COPD) and are usually used in combination with short acting medications and long acting medications in a combined inhaler.

<span class="mw-page-title-main">Bronchoconstriction</span> Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

<span class="mw-page-title-main">Metered-dose inhaler</span> Device that helps deliver a specific amount of medication to the lungs

A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for treating asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil.

<span class="mw-page-title-main">Dry-powder inhaler</span> Device that delivers medication to the lungs in the form of a dry powder

A dry-powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. DPIs are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema and COPD although DPIs have also been used in the treatment of diabetes mellitus.

<span class="mw-page-title-main">Obstructive lung disease</span> Category of respiratory disease characterized by airway obstruction

Obstructive lung disease is a category of respiratory disease characterized by airway obstruction. Many obstructive diseases of the lung result from narrowing (obstruction) of the smaller bronchi and larger bronchioles, often because of excessive contraction of the smooth muscle itself. It is generally characterized by inflamed and easily collapsible airways, obstruction to airflow, problems exhaling, and frequent medical clinic visits and hospitalizations. Types of obstructive lung disease include asthma, bronchiectasis, bronchitis and chronic obstructive pulmonary disease (COPD). Although COPD shares similar characteristics with all other obstructive lung diseases, such as the signs of coughing and wheezing, they are distinct conditions in terms of disease onset, frequency of symptoms, and reversibility of airway obstruction. Cystic fibrosis is also sometimes included in obstructive pulmonary disease.

<span class="mw-page-title-main">Pulmonary function testing</span> Test to evaluate respiratory system

Pulmonary function testing (PFT) is a complete evaluation of the respiratory system including patient history, physical examinations, and tests of pulmonary function. The primary purpose of pulmonary function testing is to identify the severity of pulmonary impairment. Pulmonary function testing has diagnostic and therapeutic roles and helps clinicians answer some general questions about patients with lung disease. PFTs are normally performed by a pulmonary function technician, respiratory therapist, respiratory physiologist, physiotherapist, pulmonologist, or general practitioner.

<span class="mw-page-title-main">Acute exacerbation of chronic obstructive pulmonary disease</span> Medical condition

An acute exacerbation of chronic obstructive pulmonary disease, or acute exacerbations of chronic bronchitis (AECB), is a sudden worsening of chronic obstructive pulmonary disease (COPD) symptoms including shortness of breath, quantity and color of phlegm that typically lasts for several days.

<span class="mw-page-title-main">Tiotropium bromide</span> Long-acting bronchodilator in the maintenance of COPD and asthma

Tiotropium bromide, sold under the brand name Spiriva among others, is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD) and asthma. Specifically it is used during periods of breathing difficulty to prevent them from getting worse, rather than to prevent them from happening. It is used by inhalation through the mouth. Onset typically begins within half an hour and lasts for 24 hours.

<span class="mw-page-title-main">Patient-controlled analgesia</span> Administration of pain relief medication by a patient

Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver an overdose of medication. Providers must always observe the first administration of any PCA medication which has not already been administered by the provider to respond to allergic reactions.

<span class="mw-page-title-main">Chronic obstructive pulmonary disease</span> Lung disease involving long-term poor airflow

Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. GOLD 2024 defined COPD as a heterogeneous lung condition characterized by chronic respiratory symptoms due to abnormalities of the airways and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.

The post bronchodilator test, also commonly referred to as a reversibility test, is a test that utilizes spirometry to assess possible reversibility of bronchoconstriction in diseases such as asthma.

Fluticasone furoate/umeclidinium bromide/vilanterol, sold under the brand name Trelegy Ellipta among others, is a fixed-dose combination inhaled medication that is used for the maintenance treatment of chronic obstructive pulmonary disease (COPD). The medications work in different ways: fluticasone furoate is an inhaled corticosteroid (ICS), umeclidinium is a long-acting muscarinic antagonist (LAMA), and vilanterol is a long-acting beta-agonist (LABA).

<span class="mw-page-title-main">Pulmonary drug delivery</span>

Pulmonary drug delivery is a route of administration in which patients use an inhaler to inhale their medications and drugs are absorbed into the bloodstream via the lung mucous membrane. This technique is most commonly used in the treatment of lung diseases, for example, asthma and chronic obstructive pulmonary disease (COPD). Different types of inhalers include metered-dose inhalers (MDI), dry powder inhalers (DPI), soft mist inhalers (SMI) and nebulizers. The rate and efficacy of pulmonary drug delivery are affected by drug particle properties, breathing patterns and respiratory tract geometry.

References

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  28. ↑ Packer KJ, Titel JH (1969). "Methoxyflurane analgesia for burns dressings: experience with the Analgizer (subscription required)". British Journal of Anaesthesia . 41 (12): 1080–5. CiteSeerX   10.1.1.1028.6601 . doi:10.1093/bja/41.12.1080. PMID   4903969.
  29. ↑ Major V, Rosen M, Mushin WW (1966). "Methoxyflurane as an obstetric analgesic: a comparison with trichloroethylene". BMJ . 2 (5529): 1554–61. doi:10.1136/bmj.2.5529.1554. PMC   1944957 . PMID   5926260.
  30. ↑ Dragon A, Goldstein I (1967). "Methoxyflurane: preliminary report on analgesic and mood modifying properties in dentistry (subscription required)". Journal of the American Dental Association. 75 (5): 1176–81. doi:10.14219/jada.archive.1967.0358. PMID   5233333.
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  32. ↑ Josephson CA, Schwartz W (1974). "The Cardiff Inhaler and Penthrane. A method of sedation analgesia in routine dentistry". Journal of the Dental Association of South Africa. 29 (2): 77–80. PMID   4534883.
  33. ↑ Babl F, Barnett P, Palmer G, Oakley E, Davidson A (2007). "A pilot study of inhaled methoxyflurane for procedural analgesia in children (subscription required)". Pediatric Anesthesia. 17 (2): 148–53. doi:10.1111/j.1460-9592.2006.02037.x. PMID   17238886. S2CID   30105092.
  34. ↑ Grindlay J, Babl FE (2009). "Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting". Emergency Medicine Australasia. 21 (1): 4–11. doi: 10.1111/j.1742-6723.2009.01153.x . PMID   19254307. S2CID   40158248.
  35. ↑ Babl FE, Jamison SR, Spicer M, Bernard S (2006). "Inhaled methoxyflurane as a prehospital analgesic in children (subscription required)". Emergency Medicine Australasia. 18 (4): 404–10. doi:10.1111/j.1742-6723.2006.00874.x. PMID   16842312. S2CID   1619160.
  36. ↑ McLennan JV (2007). "Is methoxyflurane a suitable battlefield analgesic?" (PDF). Journal of the Royal Army Medical Corps. 153 (2): 111–3. doi:10.1136/jramc-153-02-08. PMID   17896540. S2CID   38517296. Archived from the original (PDF) on 2011-07-15.
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