Evaluation of Occupational Exposure of Methoxyflurane to Paramedics in the Back of an Ontario, Canada Approved Ambulance.

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.