Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05766397 |
| Other study ID # |
CRRF 4869 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2023 |
| Est. completion date |
July 2024 |
Study information
| Verified date |
March 2024 |
| Source |
Ottawa Hospital Research Institute |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Methoxyflurane is an anesthetic gas and at low doses has shown to help with pain.
Methoxyflurane was approved in Canada in 2018. Low-dose methoxyflurane is self-administered
by patients via a handheld inhaler. Exhaled methoxyflurane is captured by an activated carbon
(AC) chamber fitted to the inhaler in order to minimize environmental and occupational
exposure. It provides rapid (<1 minute), short-term (30-45 minutes) pain relief within six to
ten inhalations and has been shown to be effective and safe in emergency care and for minor
surgical, radiological, and dental procedures.
The current dosing recommendation is 3 ml bottle. However, the frequency at which
methoxyflurane treatment can be safely used by paramedics is not established. From the
product monograph, a patient's maximum daily dose of 6 mLs and weekly 15 mLs of
methoxyflurane. The treatment course of methoxyflurane for patients should not be repeated at
an interval of less than 3 months. Despite the activated carbon chamber to capture the
exhaled methoxyflurane, when paramedics are supervising patients receiving inhaled analgesia
within a confined area (like the back of an ambulance), it is possible that a paramedic may
experience intermittent exposure to methoxyflurane vapour. Multiple use of the methoxyflurane
Inhaler, with or without the AC chamber, creates additional risk. Elevation of liver enzymes,
blood urea nitrogen, and serum uric acid, have been reported in healthcare professionals
regularly exposed to methoxyflurane inhalational products. 8 A formal limit regarding levels
of occupational exposure to methoxyflurane has not been established.
The risk of occupational exposure of methoxyflurane will be evaluated in a controlled
laboratory setting, recruiting 30 health, screened (history and blood work) volunteers to
participate in the back of an ambulance which meets the Ontario Ministry of Health Standards.
The participants will consent and follow a protocol while active samplers are placed in the
rear of the ambulance to capture the off-gassing of the methoxyflurane. This will inform the
risk of occupational exposure of methoxyflurane to paramedics, as well as, hoping to inform
the risk of multiple administrations by paramedics to different patients during a single
shift, to ensure a medical directive can be created to support patient care and evaluate and
support paramedic safety.
Description:
Background:
Pain is a common emergency that is responsible for approximately 40% of ambulance calls.1
Effective and safe relief of acute pain is not only an important medical problem; since 2004,
it is has been considered a fundamental human right.2 Yet, it is often undertreated in both
prehospital and emergency department (ED) settings.3,4 Unrelieved pain activates the
pituitary-adrenal axis, which can suppress the immune system and result in infection and poor
wound healing. 5 Sympathetic activation can have negative effects on the cardiovascular,
gastrointestinal, and renal systems, predisposing patients to adverse events such as cardiac
ischemia.5 In addition, inadequate pain management is associated with physiological and
psychological stress, which can impact therapy and rehabilitation, resulting in diminished
quality of life of the patient.6 Drugs such as nonsteroidal anti-inflammatory drugs,
ketamine, nitrous oxide, and opiates are widely used to manage acute pain by paramedics.7
Many of these treatments require higher level of paramedic training to administer, and
require expensive equipment, peripheral intravenous access and titration of analgesia, which
can be difficult without eliciting side effects.
Methoxyflurane belongs to the fluorinated hydrocarbon group of volatile anesthetic gases and
was recently approved in Canada for emergency relief of pain associated with trauma in
conscious adult patients. Methoxyflurane has analgesia properties at low doses and is rapidly
absorbed into the bloodstream to produce analgesia.14 This inhalational analgesic has been
used extensively in emergency settings in Australia and New Zealand for over 30 years. 13
Low-dose methoxyflurane is self-administered by patients in analgesic doses, at a maximum of
two 3 mL doses of methoxyflurane 99.9%, in a single administration via a handheld inhaler (a
green, whistle-shaped, single-use device).8-11 Methoxyflurane is added to the inhaler via a
one-way valve and is absorbed by a polypropylene wick. Following instruction from a trained
health care provider, the patient inhales the vaporized liquid through the mouthpiece and
exhales back into the mouthpiece. Exhaled methoxyflurane is captured by an activated carbon
(AC) chamber fitted to the inhaler in order to minimize environmental and occupational
exposure. If stronger analgesia is required, the patient can cover the dilutor hole on the AC
chamber. In vitro testing indicates that methoxyflurane concentrations delivered by the
Penthrox® inhaler can reach a peak of 0.7% when the dilutor hole on the AC chamber is closed,
and methoxyflurane concentrations are reduced by approximately 20% when the dilutor hole is
open. 12 It provides rapid (<1 minute), short-term (30-45 minutes) pain relief within six to
ten inhalations8 and has been shown to be effective and safe in emergency care13-16 and for
minor surgical, radiological, and dental procedures.9,17
Methoxyflurane was first introduced to clinical practice as an inhalation anaesthetic in
1960. 18 Its clinical use as an anaesthetic was discouraged in the late 1970s to early 1980s
due to the availability of newer anaesthetic agents and reports of dose-related renal tubular
damage following prolonged exposure to this fluorinated hydrocarbon, thought to be caused by
elevated levels of inorganic fluoride. 7,8,19 This led to its reduced use and disappearance
from anaesthetic practice by the late 1970s before being voluntarily withdrawn from the
markets in the Canada and the United States in the 1990s. 7-9 However, methoxyflurane was
never withdrawn in Australia and New Zealand where it has been available as Penthrox® for use
in lower doses as a rapid-acting analgesic for short-term pain relief. The lower analgesic
doses of methoxyflurane in laboratory and clinical data indicated no increased risk of renal
tubular damage.8 Since 1975, over five million methoxyflurane doses have been supplied. It is
used by ambulance services, first responders as a first-line analgesic agent and in brief
surgical procedures such as colonoscopies, bone marrow biopsies and changing of wound
dressings. From laboratory studies and some clinical data, lower analgesic doses of
methoxyflurane, indicated no increased risk of renal tubular damage.20
Exposure to inhaled anaesthetics is commonly assessed using the minimum alveolar
concentration (MAC). This is the concentration of inhaled anesthetic within the alveoli at
which 50% of people do not move in response to a surgical stimulus. At ≤2 MAC-hours,
methoxyflurane results in serum fluoride concentration ≤40 μmol/L which is not associated
with renal toxicity.20 The current dosing recommendation is 3 ml bottle is vaporized into the
methoxyflurane inhaler and on finishing the 3 ml dose, another 3 ml may be used, if needed.
However, the frequency at which methoxyflurane treatment can be safely used by paramedics is
not established. From the product monograph, a patient's maximum daily dose of 6 mLs and
weekly 15 mLs of methoxyflurane. 8 The treatment course of methoxyflurane for patients should
not be repeated at an interval of less than 3 months. 8 Low-dose methoxyflurane analgesic
levels, in accordance with current treatment recommendations, results in methoxyflurane
exposure of 0.6 MAC-hours, providing a 2.7 to 8-fold renal safety margin for renal toxicity.
Despite the activated carbon chamber to capture the exhaled methoxyflurane, when paramedics
are supervising patients receiving inhaled analgesia within a confined area (like the back of
an ambulance), it is possible that a paramedic may experience intermittent exposure to
methoxyflurane vapour. Multiple use of the methoxyflurane Inhaler, with or without the AC
chamber, creates additional risk. Elevation of liver enzymes, blood urea nitrogen, and serum
uric acid, have been reported in healthcare professionals regularly exposed to methoxyflurane
inhalational products. 8 A formal limit regarding levels of occupational exposure to
methoxyflurane has not been established. However, a maximum 8-hour time weighted average
(TWA) exposure level of 15 ppm was derived based on extrapolation of nephrotoxicity data from
anaesthetized patients receiving high-dose methoxyflurane.12 This benchmark is well above the
methoxyflurane odour threshold of 0.13-0.19 ppm.12 While low levels of methoxyflurane
exposure have been documented by hospital staff supervising patients using Penthrox® inhalers
during painful procedures, 12,21 studies are lacking to inform occupational exposure of
paramedics to methoxyflurane vapour during transport in the small, enclosed space of an
ambulance.
The study team conducted a feasibility study before deciding to embark on this laboratory
study and a larger-scale clinical evaluation. During the feasibility study, occupational
exposure was assessed in a real setting with consented paramedics. As this study was
conducted pragmatically during ambulance calls, study was unable to determine when
methoxyflurane was going to be used. Therefore, despite 30 samples being placed in
ambulances, our study analyzed seven samples. Two were field blanks (i.e. no methoxyflurane
was used during the paramedic shift) and two samples were controls and were never open but
went through analysis. For the remaining three samples, the time of administration was 20
minutes, 16 minutes and 10 minutes. Each sampler was evaluated on a 720 minute exposure
period resulting in a mean concentration of 0.0912 ppm (minimum=0.0147 and maximum 0.186
ppm). No exposures above the maximum exposure limit (MEL) of 15 ppm (8 TWA) were noted. The
field blanks as well as the controls recorded <3ng when analyzed. These findings are
consistent with other studies12 which showed levels of vapour capture below the ceiling limit
of 2 ppm. Frangos et al. reported a mean 8-hour TWA methoxyflurane exposure by flight
paramedics to be 0.23 ppm without the activated charcoal chamber within a confined ambulance
and well below the MEL of 15 ppm. 12 This real-world study, conducted in the prehospital
setting in the back of an ambulance, showed well below safe levels of methoxyflurane vapour
exposure to paramedics. However, there is still a gap in knowledge on understanding this
exposure and the cumulative risk of methoxyflurane administered multiple times during a
paramedic's shift.
II- OBJECTIVES The risk of occupational exposure of methoxyflurane will be evaluated in a
controlled laboratory setting, using an ambulance which meets the Ontario Ministry of Health
Standards. 22 This will inform the risk of occupational exposure of methoxyflurane to
paramedics, as well as, hoping to inform the risk of multiple administrations by paramedics
to different patients during a single shift, to ensure a medical directive can be created to
support patient care and evaluate and support paramedic safety.
The aim of this non-clinical laboratory-controlled study is to evaluate the risk, considering
a maximum exposure limit (MEL) of 15 ppm (8-hour TWA), of occupational exposure of
methoxyflurane in the back of an enclosed ambulance with single and multiple events.
III- METHODS Design This is a phase other, Health Canada regulated, non-clinical occupational
exposure laboratory study, where healthy human participants will inhale methoxyflurane and
during which occupational exposure of methoxyflurane will be measured via strategically
positioned samplers (active and passive) according to a pre-set protocol, including single
and multiple consecutive events.
Setting The study will be conducted in the back of a ministry approved ambulance where,
according to the Ontario Provincial Land Ambulance & Emergency Response Standard, (REF) it
requires the ventilation system(s) be capable of providing a complete change of ambient air
within the vehicle every 2.5 minutes with the vehicle static. Ventilation shall be separately
controlled within each compartment.22 The approximate cubic meter volume in the driver and
patient compartment is 15 m3. The front and rear compartment are separated by a bulkhead with
a communication window between the driver compartment and patient compartment.
Participants Recruitment A plain (lay) language posting in English will be developed, using a
template from the Ottawa Hospital Research Institute (OHRI). The Ottawa Hospital (TOH)
corporate social media and work with OHRI's media leads to assist with posters and other TOH
available advertising to recruit interested participants to the study. These digital postings
will have a phone number and email for interested participants to contact the research team.
A research team member will contact the interested participant and complete the primary
screening process and consent the participant to participate in the study. A standard
clinical trial informed consent form from OHRI will be used. Once consent is complete the
research team will send the participant a link to a participant enrollment form, developed
using Microsoft Forms, to complete. All information regarding study participants will be kept
on a secure server on the TOH SharePoint for a minimum of 15 years, only accessible by the
research study team members. If the participant meets the primary screening criteria, has
consented and has completed the enrollment form, they will move onto the secondary
(laboratory) screening process.
Screening A standard protocol for screening the participants will be used. See flow diagram
(appendix 1) for details. Inspiratory capacity and expiratory reserve volumes are similar
among males ages ≥18 similarly among females ≥18.23 Therefore, age is not considered to bias
or impact study results. Equal distribution across sexes when enrolling volunteers.
