Ignite Creation Date:
2024-05-06 @ 6:45 PM
Last Modification Date:
2024-10-26 @ 2:53 PM
Study NCT ID:
NCT05766397
Status:
ENROLLING_BY_INVITATION
Last Update Posted:
2024-03-21
First Post:
2023-02-21
Brief Title:
Prehospital Inhaled Methoxyflurane Non-Clinical Occupational Exposure Study
Sponsor:
Ottawa Hospital Research Institute
Organization:
Ottawa Hospital Research Institute
Study Overview
Official Title:
Evaluation of Occupational Exposure of Methoxyflurane to Paramedics in the Back of an Ontario Canada Approved Ambulance
Status:
ENROLLING_BY_INVITATION
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 patients 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
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 patients 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
Detailed Description:
Background
Pain is a common emergency that is responsible for approximately 40 of ambulance calls1 Effective and safe relief of acute pain is not only an important medical problem since 2004 it is has been considered a fundamental human right2 Yet it is often undertreated in both prehospital and emergency department ED settings34 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 ischemia5 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 patient6 Drugs such as nonsteroidal anti-inflammatory drugs ketamine nitrous oxide and opiates are widely used to manage acute pain by paramedics7 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 analgesia14 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 999 in a single administration via a handheld inhaler a green whistle-shaped single-use device8-11 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 07 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 procedures917
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 7819 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 damage8 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 damage20
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 μmolL which is not associated with renal toxicity20 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 patients 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 06 MAC-hours providing a 27 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 methoxyflurane12 This benchmark is well above the methoxyflurane odour threshold of 013-019 ppm12 While low levels of methoxyflurane exposure have been documented by hospital staff supervising patients using Penthrox inhalers during painful procedures 1221 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 ie 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 00912 ppm minimum00147 and maximum 0186 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 023 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 paramedics 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 systems be capable of providing a complete change of ambient air within the vehicle every 25 minutes with the vehicle static Ventilation shall be separately controlled within each compartment22 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 OHRIs 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 1823 Therefore age is not considered to bias or impact study results Equal distribution across sexes when enrolling volunteers
Pain is a common emergency that is responsible for approximately 40 of ambulance calls1 Effective and safe relief of acute pain is not only an important medical problem since 2004 it is has been considered a fundamental human right2 Yet it is often undertreated in both prehospital and emergency department ED settings34 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 ischemia5 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 patient6 Drugs such as nonsteroidal anti-inflammatory drugs ketamine nitrous oxide and opiates are widely used to manage acute pain by paramedics7 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 analgesia14 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 999 in a single administration via a handheld inhaler a green whistle-shaped single-use device8-11 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 07 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 procedures917
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 7819 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 damage8 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 damage20
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 μmolL which is not associated with renal toxicity20 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 patients 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 06 MAC-hours providing a 27 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 methoxyflurane12 This benchmark is well above the methoxyflurane odour threshold of 013-019 ppm12 While low levels of methoxyflurane exposure have been documented by hospital staff supervising patients using Penthrox inhalers during painful procedures 1221 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 ie 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 00912 ppm minimum00147 and maximum 0186 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 023 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 paramedics 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 systems be capable of providing a complete change of ambient air within the vehicle every 25 minutes with the vehicle static Ventilation shall be separately controlled within each compartment22 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 OHRIs 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 1823 Therefore age is not considered to bias or impact study results Equal distribution across sexes when enrolling volunteers
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None