SGEM#320: The RAMPED Trial – It’s a Gas, Gas, Gas

Date: February 18th, 2021 Guest Skeptic: Dr. Chris Bond is an emergency medicine physician and assistant Professor at the University of Calgary. He is also an avid FOAM supporter/producer through various online outlets including TheSGEM. Reference: Brichko et al. Rapid Administration of Methoxyflurane to Patients in the Emergency Department (RAMPED): A Randomised controlled trial of Methoxyflurane vs Standard care. AEM Feb 2021. Case: A 46-year-old female presents to the emergency department (ED) with sudden onset, severe right flank pain. She is pacing around at triage in tears and says she has a history of kidney stones. She is asking for something to help with her pain, but the department is very busy, and it will be some time before she can get into a treatment space. Background: Pain is the primary reason patients present to the emergency in many cases (1-6).  Oligoanalgesia is the term used to describe poor pain management through the under use of analgesia (7-11).  Effective pain management is an important indicator of the quality of patient care (12). Multiple factors have been thought to contribute to oligoanalgesia (overcrowding, language barriers, age, gender, ethnicity, insurance status) (13-16).  Delays in providing adequate analgesia leads to poorer patient outcomes, prolonged ED length of stay and reduced patient satisfaction (17, 18). It can take a long time for someone in severe pain to receive an analgesic in the ED. Previous research in Australia has shown that the median time can be between 40-70 minutes for analgesia administration (19, 20). Delays are not unique to Australia and a study done in the USA reported a mean of 116 minutes for patients presenting to the ED with pain to receive analgesia (21). To minimize delays, different strategies have been implemented to address the problem (advanced protocols, provision of oral analgesics at triage, and the use of novel analgesic agents that do not require intravenous access) (22). Recently, there has been increased interest in using methoxyflurane (Penthrox), an inhaled non-opioid analgesic, to provide rapid short-term analgesia (23, 24).  In Australia, Methoxyflurane has been widely used at sub-anesthetic doses for analgesia in the pre-hospital setting since 1975. Its use has become more global in recent years and at low doses, it has a very reassuring safety profile. Furthermore, there have been no reports of addiction or abuse related to these inhaler devices (25-28). The majority of studies of methoxyflurane for pain focus on traumatic pain, this study aimed to assess its effectiveness in treatment of both traumatic and non-traumatic pain. Clinical Question: What is the effectiveness of methoxyflurane versus standard care for the initial management of severe pain among adult ED patients? Reference:  Brichko et al. Rapid Administration of Methoxyflurane to Patients in the Emergency Department (RAMPED): A Randomised controlled trial of Methoxyflurane vs Standard care. AEM Feb 2021. Population: Adult patients aged 18-75 years with severe pain defined as an initial Numerical Rating Scale (NRS) pain score greater than or equal to 8. Exclusion criteria: Transferred patients, HR <40 or >140 bpm, SBP <90 or >180 mmHg, RR <6 or >36/min, GCS <15, possible ACS, headache, pregnancy, breastfeeding, known renal or hepatic failure, previous malignant hyperthermia, known sensitivity to fluorinated anesthetics, or agitated/aggressive per nursing staff. Intervention: Inhaled Methoxyflurane 3 mL Comparison: Standard analgesic care which could include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and oral oxycodone or IV morphine Outcome: Primary Outcome: Proportion of patients that had at least a 50% reduction in their pain score at 30 minutes Secondary Outcomes: Median pain score at 15, 30, 60 and 90 minutes, and the proportion of patients that achieved a >2 point drop in their pain score on the NRS. Additional secondary outcomes included data pertaining to adverse effects, both minor and major. Dr. Lisa Brichko This is an SGEMHOP episode which means we have the lead author on the show. Dr Lisa Brichko is an emergency physician working in a combination of private and public tertiary hospital Emergency Departments in Melbourne Australia. She has authored 24 peer-reviewed emergency medicine research publications primarily focusing on projects promoting safe and efficient patient care. This interest in improving the quality of care we can provide our emergency department patients has previously been developed through undertaking a Masters Degree in Health Management, attaining Associate Fellowship with the Royal Australasian College of Medical Administrators and her current role as Quality Improvement Manager on the emergency department leadership team for Cabrini Hospital. Authors’ Conclusions: “Initial management with inhaled methoxyflurane in the ED did not achieve the pre-specified substantial reduction in pain, but was associated with clinically significant lower pain scores compared to standard therapy.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Unsure The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). No The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Key Results: They randomized 121 patients into the RAMPED study and data was available for analysis in 120 patients. The mean patient age was 42 years and 51% were female. 84% of patients were enrolled during daytime hours (0700-1800). The vast majority of patients arrived by private transport with only 4% arriving by ambulance. There was no statistical difference in the primary outcome between methoxyflurane and standard care. Primary Outcome: Reduction of pain score by >50% at 30 minutes 6 (10%) of patients in the methoxyflurane arm and 3 (5%) in the standard care arm (p=0.49) Hazard ratio (HR) for the favourable outcome was 1.07 (95% CI: 0.75-1.53, p=0.70) Secondary Outcomes:  The administration of methoxyflurane was associated with a significant reduction in pain score at all time points. See the show notes for table. The median time to rescue analgesia was longer in the methoxyflurane arm at 66 minutes compared to 46 minutes in the standard therapy arm (p=0.024) There were no serious adverse effects that could be attributed to the intervention and median ED LOS was similar between the two groups. We have ten nerdy questions for Lisa to help us better understand her study. Listen to her respond to each question on the SGEM podcast. 1. Convenience Sample: This was a convenience sample when research assistants were available. Do you think this could have impacted the results and if so, in what way? 2. Arrival: The vast majority (96%) of included patients in the cohort arrived by private vehicle. Only 4% of patients were brought in by ambulance. This number seems low to us. What this surprising to your team? Do you think this low number limits the generalizability of your results? 3. This One Goes to Eleven: Different outcome measures in pain trials have been used (29). Why did you choose an 11-point numerical ratings scale (NRS) for pain rating over other options (eg. Visual analogue scale)? 4. Age: One of your exclusion criteria was age. Why did you decide to exclude patients younger than 18 years of age and also those >75 years of age? There is evidence that children and older adults are at more risk for oligoanalgesia. 5. Hemodynamics: Another exclusion for your study was hemodynamic instability. This was defined as a heart rate < 40 or > 140 beats/min or a systolic blood pressure < 90 or> 180 mm Hg, I did not think methoxyflurane had a clinically significant impact on HR and BP (30). 6. Outcome: You measured the NRS up to 90 minutes. Would measuring time points beyond 90 minutes be useful in order to see if patients did not have adequate analgesia after 90 minutes? 7. Blinding: You did not have an active or placebo control (sham) in an attempt to blind this trial. All clinicians and participants were aware of group allocation. This could have biased the study. We understand the ethical concerns about using a placebo control (inhaled 0.9% saline) for patients with painful conditions. Did you consider having inhaled nitrous oxide as an active comparator? 8. Cost: Cost can be an important factor when considering a treatment modality in the ED. We say that with IV acetaminophen it was priced too high for broad adaptation in the USA. Do you know what the cost of methoxyflurane is compared to standard care? 9. Malignant Hyperthermia: Methoxyflurane is a volatile anaesthetic agent. It has the potential to trigger malignant hyperthermia. There has apparently only been only one incident of MH after administration in Australia (31).  Regardless, methoxyflurane is still contraindicated in those individuals thought to at risk for malignant hyperthermia (32). How concerned should we be about using this medication, and do you need to stock dantrolene because of the risk? 10. Aerosolizing: We are still in a global pandemic. Is there any concern to using this inhaler during COVID19?