Administration Of Methoxyflurane Research Articles

Deployed Combat Use of Methoxyflurane for Analgesia.

The U.S. Military needs fast-acting, non-opioid solutions for battlefield pain. The U.S. Military recently used morphine auto-injectors, which are now unavailable. Off-label ketamine and oral transmucosal fentanyl citrate use introduces challenges and is therefore uncommon among conventional forces. Sublingual suftentanil is the only recent pain medication acquired to fill this gap. Conversely, methoxyflurane delivered by a handheld inhaler is promising, fast-acting, and available to some partner forces. We describe methoxyflurane use reported in the Department of Defense Trauma Registry (DODTR). We requested all available DODTR encounters from 2007 to 2023 with a documented intervention or assessment within the first 72 hours of care. We analyzed casualties who received methoxyflurane in the prehospital setting using descriptive statistics. There were 22 encounters with documented methoxyflurane administration. The median patient age was 23 (range 21-31) years. All were men. The largest proportion was partner force (50%), followed by U.S. Military (27%). Most (64%) sustained battle injuries. Explosives were the most common mechanism of injury (46%), followed by firearms (23%). The median injury severity score was 5 (range 1-17). The most frequent injuries were serious injuries to the extremities (27%), and 23% of patients (5) received a tourniquet. One-half of the casualties received concomitant pain medications. Only three casualties had multiple pain scores measured, with a median pain score change of -3 on a scale of 10. Methoxyflurane use in deployed combat shows both feasibility and usability for analgesia.

Pain Management with Inhalation of Methoxyflurane Administrated by Non-Medical Ski Patrol: A Quality Assessment Study.

Pain management can be challenging, especially in remote locations where first responders are not certified health care personnel. In these settings, traditional intravenous administration of analgesics is not feasible. In this study, we explore the feasibility of using methoxyflurane as a first-line analgesic in ski-related traumas, administered by the ski patrol, acting as the municipality physician's aiding personnel. This is a quality assessment of a project aimed at improving pain management in trauma patients at the largest ski resort in Norway. Members of the ski patrol were trained and delegated administration of methoxyflurane on behalf of the municipality physician. Patients > 18years with ski-related trauma and pain Numeric Rating Scale (NRS) of 6 or more were included. The patients received inhalational methoxyflurane on site, with continued administration during transport. Data were collected by the ski patrol and entered into a quality register. In total, 53 patients (18 to 76years, 32 (60%) males) accepted to be registered. The injuries were fractures in 35 (66%), joint luxation in seven (13%), combination of fracture and luxation in seven (13%), and blunt soft tissue damage in four (8%) cases. Median NRS before administration of methoxyflurane was 8 decreasing to median NRS 5 after 5-10min. The median NRS reduction of 3 (25-75% percentiles 2-5) was significant, p < 0.001. Patients rated the perceived effect as good in 40 (80%) moderate in nine (18%) and no effect in 1 (2%). Side effects were mild: Six patients (11%) experienced dizziness, one patient (2%) was considered drowsy. Methoxyflurane is feasible as a first-line analgesic administered by a non-medical ski patrol in a responsibly organized system. Early pain management with inhalation of methoxyflurane provides good perceived effect with mild adverse events and can be of great value in settings where few alternatives for pain management are available.

Serum fluoride levels in ambulance staff after commencement of methoxyflurane administration compared to meta-analysis results for the general public.

Ambulance officers administering methoxyflurane as an inhalational analgesic may be exposed to trace vapor. Fluoride is a methoxyflurane metabolite, and has been associated with acute renal failure in anesthesia patients and skeletal fluorosis with chronic elevated serum levels from other sources. However, there has been no direct measurement of serum fluoride in occupationally exposed ambulance officers. Thus, this study directly measures serum fluoride over a prolonged period in order to determine renal toxic and skeletal fluorosis risk to ambulance officers who are administering methoxyflurane. Serum inorganic fluoride concentrations were measured in a prospective observational study of 12 emergency medical technicians (EMTs). The study took 7 serum fluoride measurements over 24 months. A meta-analysis of healthy adult serum fluoride ranges was also conducted. The typical healthy adult serum fluoride range was determined to be 0.21-2.11 μmol/l (p < 0.001). The EMTs' baseline median (IQR) serum fluoride concentrations were 0.4 μmol/l (0.2; 1.0) with maximum 1.6 μmol/l. The EMTs' overall median serum fluoride was 0.4 μmol/l (0.2; 1.3) with maximum 4.0 μmol/l, usually within healthy reference ranges. All results were ≤10% of the suggested single-dose renal toxic threshold. One result was above a threshold for skeletal fluorosis. The highest measured serum fluoride was 24% of the lowest level associated with radiologic evidence of fluorosis. There was no evidence overall of increasing serum fluoride levels. There was no evidence that EMTs' exposure to methoxyflurane resulted in sustained increased serum fluoride. These results imply EMTs' occupational safety from acute renal toxicity when activated carbon filtration is used on patient exhalation. However, 1 serum fluoride result above a skeletal fluorosis threshold suggests that the risk of mild skeletal fluorosis cannot be excluded. Int J Occup Med Environ Health. 2021;34(6):767-77.

A bootstrap approach for predicting fluoride toxicity in paramedics after occupational methoxyflurane exposure

Background:Methoxyflurane is an anaesthetic that can cause dose-related patient nephrotoxicity. It was withdrawn from anaesthetic use approximately 40 years ago. It is now only administered for analgesia, via inhaler devices. Ambulance officers can be exposed to methoxyflurane vapour during methoxyflurane administration. While extrapolation from data of anaesthetised patients implied occupational exposure was safe, this may be doubtful and requires further verification.Approach — Patient data from four anaesthesia studies were combined. A bootstrap analysis of the combined data was used to form a probabilistic inference of the risk posed to ambulance officers.Findings — Due to extrapolation over 2–5 orders of magnitude of exposure from the source data, there was a very low precision in the likely risk. Both the linear and power law models exhibited non-zero risk, of 8.7% and 0.3% toxicity risk respectively, for a single exposure in the likely occupational range. This suggests that the safety of occupational exposure cannot be firmly established with this type of extrapolation analysis. Furthermore, this approach does not account for repeated exposures, or outlier events. Conclusion:Data from anaesthesia studies is inadequate for extrapolation to occupational exposure. Consequently, risks for ambulance officers need to be reappraised. There is a need for further empirical study to determine the exposure of ambulance officers and other healthcare staff.

Methoxyflurane (Penthrox®)—a case series of use in the prehospital setting

Methoxyflurane (Penthrox®) is a fluorinated hydrocarbon, which when first used in general anaesthesia was noted to have strong analgesic properties in subanaesthetic dosage. More than 5 million doses have been sold for use in Australia since 1978 and have been found to have an excellent safety profile. After rigorous review by the Medicines and Healthcare Regulatory Agency, methoxyflurane was granted a product licence in 2015 in the UK and Europe for the relief of pain in patients with moderate-to-severe trauma. This paper presents the first reported case series of patients treated with methoxyflurane in the UK and Ireland in the prehospital environment. The results show a statistically significant improvement in patient pain scores at 1, 2 and 5 minutes following administration of methoxyflurane. With its use increasing in prehospital care and emergency departments, methoxyflurane is recognised as a useful adjunct to the choice of analgesia for trauma patients with moderate-to-severe pain.

The volatile anesthetic methoxyflurane protects motoneurons against excitotoxicity in an in vitro model of rat spinal cord injury

Neuroprotection of the spinal cord during the early phase of injury is an important goal to determine a favorable outcome by prevention of delayed pathological events, including excitotoxicity, which otherwise extend the primary damage and amplify the often irreversible loss of motor function. While intensive care and neurosurgical intervention are important treatments, effective neuroprotection requires further experimental studies focused to target vulnerable neurons, particularly motoneurons. The present investigation examined whether the volatile general anesthetic methoxyflurane might protect spinal locomotor networks from kainate-evoked excitotoxicity using an in vitro rat spinal cord preparation as a model. The protocols involved 1h excitotoxic stimulation on day 1 followed by electrophysiological and immunohistochemical testing on day 2. A single administration of methoxyflurane applied together with kainate (1h), or 30 or even 60min later prevented any depression of spinal reflexes, loss of motoneuron excitability, and histological damage. Methoxyflurane per se temporarily decreased synaptic transmission and motoneuron excitability, effects readily reversible on washout. Spinal locomotor activity recorded as alternating electrical discharges from lumbar motor pools was fully preserved on the second day after application of methoxyflurane together with (or after) kainate. These data suggest that a volatile general anesthetic could provide strong electrophysiological and histological neuroprotection that enabled expression of locomotor network activity 1day after the excitotoxic challenge. It is hypothesized that the benefits of early neurosurgery for acute spinal cord injury (SCI) might be enhanced if, in addition to injury decompression and stabilization, the protective role of general anesthesia is exploited.

022 Methoxyflurane: would giving the “Green Whistle” the green light benefit mountain casualties in Snowdonia?

Objectives and BackgroundsMethoxyflurane, currently licensed only in Australasia, is a convenient, rapidly effective pre-hospital analgesic, although it achieves inferior pain reduction compared to intravenous morphine or intranasal fentanyl. Methoxyflurane in...

Gas Anesthesia Setup for Methoxyflurane Use in Small Rodents

We describe here a simple, inexpensive method for the administration of methoxyflurane (Metofane) inhalant to small rodents. This system can be safely used to provide a relatively rapid induction (1-5 minutes) of anesthesia. A metal chamber is constructed to comfortably accommodate the animal to be anesthetized. The chamber contains a hard plastic lid that can slide open for introducing or retrieving the animal. The chamber has two male-type openings, one on either side (see Figure 1). The first opening (A), on the upper end of the chamber, is used for exhausting the anesthetic (kept closed during the induction period). The second (B), on the lower portion, functions as a gas inlet. A segment of Tygon tubing connects the gas inlet opening to a gas wash bottle (C). The opposite fitting of the wash bottle is connected to an Erlenmeyer flask (D) via Tygon tubing. The flask is partially filled with distilled water and fitted with a rubber stopper that bears two holes. The holes are used to hold two glass or metal hollow cylindrical rods. One shorter rod (E) fits into a hole and sits above the water line. This rod is connected to the inlet tube (D) of the gas wash bottle. The second rod (F) sits below the water level in the Erlenmeyer flask. It is connected to a pump so that the air coming in will be humidified. The anesthetic must be at least 1 inch above the fritted disk of the gas wash bottle. All tubing connections should be sealed to prevent any gas leakage. The system should be placed in a fume hood to ensure minimal gas leakage into room air. The exhaust hole may also be used to supply anesthetic for a face mask or nose cone. Just attach a piece of tubing to the exhaust opening (A), and use that to cover the nose or face of the animal to be kept under anesthesia. We have anesthetized rats, mice, and guinea pigs using this system and have had great success. The animals are inducted smoothly with no physical restraint required, and recovery is quick. Benefits to the scientist include less exposure to gas and ease of use.

The Effect of Cimetidine on Anesthetic Metabolism and Toxicity

Because the H2-receptor antagonist cimetidine has been shown to inhibit drug metabolism, the effects of cimetidine on anesthetic metabolism and toxicity were investigated in a rat model. Cimetidine decreased inorganic plasma fluoride production after methoxyflurane administration both in 21% oxygen (P less than 0.001) and in 100% oxygen (P less than 0.001). Phenobarbital produces an increased fluoride formation after methoxyflurane anesthesia, and this fluoride formation is also reduced by cimetidine (P less than 0.005). There was no significant difference between the plasma fluoride levels in rats anesthetized with halothane or enflurane. Although cimetidine inhibited the in vivo defluorination of methoxyflurane, fluoride levels were still within the nephrotoxic range, and cimetidine is not likely to play a role as part of a preanesthetic regimen that would permit the increased clinical use of methoxyflurane. Cimetidine also inhibited the oxidative metabolism of halothane; cimetidine decreased (P less than 0.05) trifluoroacetic acid concentrations after halothane anesthesia in 21% oxygen and in 100% oxygen and decreased (P less than 0.05) bromide concentrations after halothane anesthesia in 100% oxygen. Trifluoroacetic acid levels were less (P less than 0.02) after halothane anesthesia in 14% oxygen as compared with 100% oxygen, indicating a reduction in oxidative metabolism under hypoxic conditions. However, bromide concentrations were maximal after halothane anesthesia in 21% oxygen, and significantly (P less than 0.001) less after halothane anesthesia in 14% and 100% oxygen. Bromide production, therefore, seems to be inhibited by both hypoxia and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluorinated anaesthetic nephrotoxicity: an update

The potential for fluorinated anaesthetic agents to cause nephrotoxicity can be summarized in two figures: Figure 2 illustrates the time course of anaesthetic defluorination following administration of methoxyflurane, enflurane and isoflurane; Figure 5 depicts changes in urinary osmolality in response to ADH administration versus peak serum fluoride levels after anaesthesia. Figure 2 clearly demonstrates that the shapes of the serum inorganic fluoride curves are different after methoxyflurane, enflurane and isoflurane anaesthesia. Despite the fact that inorganic fluoride has a half life in blood of only 90 minutes, peak levels were maintained for three days after administration of methoxyflurane. By contrast, peak fluoride levels after administration of the other two agents were reached shortly after the end of anaesthesia and they declined rapidly in the postanaesthetic period. To account for the prolonged postanaesthetic elevation of fluoride levels, one only must realize that methoxyflurane is approximately ten times more lipid soluble than either enflurane or isoflurane. Thus, methoxyflurane is present in the body for days after its administration has ended and is available for postoperative metabolism to inorganic fluoride. Peak fluoride levels also are considerably higher after methoxyflurane anaesthesia than after administration of the other two agents. That is because, on a molar basis, methoxyflurane is biochemically more unstable than either enflurane or isoflurane and is metabolized more per unit of time. Consequently, the area under the fluoride curve is much greater after methoxyflurane anaesthesia than after either enflurane or isoflurane. It is the area under the curve which probably best correlates with nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Nephrotoxicity of Fluorinated Anaesthetic Agents

SUMMARY The subject of fluorinated anaesthetic nephrotoxicity can be summarized in two figures. Figure 6 illustrates the time-course of anaesthetic defluorination following administration of methoxyflurane, enflurane and isoflurane. Figure 9 depicts changes in urinary osmolality in response to ADH administration in relationship to peak serum inorganic fluoride levels after anaesthesia. Figure 6 clearly demonstrates that the shapes of the serum inorganic fluoride curves are different after methoxyflurane, enflurane and isoflurane anaesthesia. Despite the fact that inorganic fluoride has a half-life of only 90 minutes, peak levels were maintained for three days after administration of methoxyflurane. In contrast, peak inorganic fluoride serum levels after administration of the other two agents were reached shortly after the end of anaesthesia and declined rapidly in the postanaesthetic period. To account for this prolonged elevation of fluoride levels, one has only to realize that methoxyflurane is approximately ten times more lipid soluble than either enflurane or isoflurane and that the great majority of methoxyflurane metabolism occurs in the postoperative period. Peak fluoride levels also are considerably higher after methoxyflurane anaesthesia than after administration of the other two agents. That is because methoxyflurane is biochemically more unstable than either enflurane or isoflurane and is metabolized more per unit time. Consequently, the area under the serum inorganic fluoride curve is much greater for methoxyflurane than it is for enflurane and isoflurane. Figure 9 demonstrates the strong correlation between changes in urinary osmolality after ADH administration and serum inorganic fluoride levels. Patients anaesthetized with halothane, in whom serum inorganic fluoride levels ranged from 1 to 3 /zM, showed a small increase in urinary osmolality. Volunteers anaesthetized with enflurane, in whom fluoride levels were 3 to 5 μM five days after anaesthesia, showed no change in maximum urinary osmolality, whereas an average decrease of approximately 250 mosmol/kg was seen the day after anaesthesia when the mean fluoride level was 33.6 /zM. Following high-dose methoxyflurane anaesthesia, fluoride levels ranged from 80 to 250 μM and the decrement in maximum urinary concentrating ability ranged from 400 to 600 mosmol/kg. It appears that the answers to the questions regarding inorganic fluoride nephrotoxicity are clear. Methoxyflurane is a dose-related nephrotoxin; its use should be reserved for clinical situations where it is specifically indicated, such as when a potent inhalational analgesic agent is required and when total dosage will be low (less than 2 MAC hours). Enflurane would appear to be safe in all patients, including those with mild to moderate renal impairment.

Methoxyflurane-induced nephrotoxicity: Influence of food intake on some biochemical indicators of renal function in Fischer 344 rats

The effect of methoxyflurane (MOF) anesthesia on food and water intake was measured in Fischer 344 rats which had been placed in an inhlation chamber containing 0.5% MOF for exposure times up to 6 hr. Pair-fed control rats were used to determine the role food intake plays in the renal toxicity observed after MOF administration. MOF anesthesia caused a dose-related decrease in the daily food consumption, body weight, and urinary osmolality, and an increase in the daily water intake and 24-hr urine volume. Administration of 0.5% MOF caused the daily food consumption to drop from 16.1 to 0.5 g/day/rat. Restricting the amount of food consumed per day by sham-treated Fischer 344 rats caused a decrease in body weight, daily water intake, and urine osmolality without changing the 24-hr urine volume (food deprivation for periods greater than 2 days resulted in a significant reduction in the 24-hr urine output). In MOF-treated rats, the increase in urine volume occurred prior to the increase in water intake. The loss in body weight and the decrease in excretion of solutes in the urine was the same for MOF-treated and pair-fed rats. The polyuria and polydipsia in MOF-treated rats was a result of the treatment unrelated to changes in daily food consumption.

Effect of Enzyme Induction on Nephrotoxicity of Halothane-Related Compounds

Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent.

Effect of enzyme induction on nephrotoxicity of halothane-related compounds.

Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent.

Methoxyflurane nephropathy.

Investigations of methoxyflurane-induced nephrotoxicity in man have been extensively aided by the use of an animal model. To be of value the animal model must share similar metabolic pathways with man and have the same clinical manifestations of the diseases process. The Fischer 344 rat appears to meet these criteria. The predominant factors in the production of methoxyflurane nephrotoxicity appear to be high methoxyflurane dosage and serum inorganic fluoride concentration. It is likely that secondary factors include: (1) a high rate of methoxyflurane metabolism and sepsitivity of the kidney to inorganic fluoride toxicity: (2) concurrent treatment with other nephrotoxic drugs; (3) preexisting renal disease; (4) surgery of the urogenital tract, aorta, or renal vasculative; (5) repeat administration of methoxyflurane due to accumulation of inorganic fluoride and, perhaps, methoxyflurane induction of its own metabolism: and (6) concurrent treatment with enzyme-inducing drugs such as phenobarbital.

Methoxyflurane Nephropathy

Investigations of methoxyflurane-induced nephrotoxicity in man have been extensively aided by the use of an animal model. To be of value the animal model must share similar metabolic pathways with man and have the same clinical manifestations of the diseases process. The Fischer 344 rat appears to meet these criteria. The predominant factors in the production of methoxyflurane nephrotoxicity appear to be high methoxyflurane dosage and serum inorganic fluoride concentration. It is likely that secondary factors include: (1) a high rate of methoxyflurane metabolism and sepsitivity of the kidney to inorganic fluoride toxicity: (2) concurrent treatment with other nephrotoxic drugs; (3) preexisting renal disease; (4) surgery of the urogenital tract, aorta, or renal vasculative; (5) repeat administration of methoxyflurane due to accumulation of inorganic fluoride and, perhaps, methoxyflurane induction of its own metabolism: and (6) concurrent treatment with enzyme-inducing drugs such as phenobarbital.

Methoxyflurane biotransformation and renal function following methoxyflurane administration for vaginal delivery or cesarean section.

Methoxyflurane (MOF) administration for conscious analgesia during vaginal delivery (range 5 to 70 min, mean 23 min) or for anesthesia following delivery of the infant at cesarean section (range 25 to 70 min, mean 44 min) was studied in 18 healthy parturients. Serum ionic fluoride increased significantly in both groups 2 hours after discontinuing MOF with peak concentrations of 11.2 and 14.1 mumol/L in the vaginal delivery and cesarean section groups, respectively. Individual peak serum ionic fluoride levels in the 2 groups of 21 and 25 mumol/L were well below reported levels for subclinical toxicity. Significant ionic fluoride elevations in fetal umbilical venous blood (mean 5.3 mumol/L) were measured in the vaginal-delivery group. Maternal urinary ionic fluoride and oxalate were elevated 24 and 48 hours postpartum. BUN, creatinine, urine volume, and urine osmolality remained within normal range. These data indicate that hazardous elevations of serum ionic fluoride with subsequent renal dysfunction are unlikely following low-dose MOF administration for vaginal delivery or cesarean section.

THE ETIOLOGY OF METHOXYFLURANE NEPHROTOXICITY

COUSINS, M. J.; MAZZE, R. I.; KOSEK, J. C.; HITT, B. A.; LOVE, F. V. Author Information

Methoxyflurane nephrotoxicity. A study of dose response in man.

Dose-related abnormalities in renal function occurred in ten of 18 patients following administration of methoxyflurane (Penthrane) with the usual anesthetic adjuvants. Eight control patients anesthetized with halothane (Fluothane) showed no abnormalities in renal function. Subclinical toxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours, that is 2.5 to 3 MAC hours (serum inorganic fluoride, >50 micromols/liter), while clinical toxicity was present in all patients at dosages greater than five MAC hours (serum inorganic fluoride, >90 micromols/liter). Superimposed on the dose-response relationship were other factors that probably increased nephrotoxicity. These were as follows: individual variations in metabolism of methoxyflurane; increased sensitivity to the nephrotoxic effects of inorganic fluoride; presence of enzyme induction; and interaction of methoxyflurane with other nephrotoxic drugs. The use of methoxyflurane in clinical anesthesia should be restricted to situations where it offers specific advantages and where dosages less than 2.5 MAC hours can be attained.

A New Circuit Injection Technic for Syringe-Measured Administration of Methoxyflurane

A New Circuit Injection Technic for Syringe-Measured Administration of Methoxyflurane