You’re on a shift in the Rapid Response Vehicle. The radio crackles to life; a two-year-old has pulled a chest of drawers onto himself. He’s conscious and breathing, but his leg is badly injured. Lights and sirens are on, and you wonder what will greet you.
The challenge of prehospital analgesia
Assessing children in the prehospital environment can be challenging. As strangers arriving at a child’s house when they feel unwell, hurt, or scared, we can seem frightening. Attending multi-patient scenarios, such as a road traffic collision, where both child and parent are injured, poses additional challenges. Separating a child from their parent to attend different adult and paediatric hospitals can be hugely traumatic for the child (and the carer ). Although we try to get another adult to the scene to accompany the child to the hospital, this isn’t always possible.
In the prehospital setting, we don’t have the luxury of time. So a quick decision needs to be made: is this child sick or not sick?
For many prehospital clinicians, children make up a very small proportion of their workload. Drawing up paediatric-drug doses and administering these medications to a scared child takes training and practice.
All of this can make a clinical assessment of a child difficult. Taking off the high-vis jacket, getting down to the child’s level, creating a glove-balloon character and using bubbles can all help a child feel at ease.
The prehospital assessment toolbox
There are some validated tools in our box to help overcome these challenges. For example, the Paediatric Assessment Triangle has been used by prehospital care providers at all levels for many years, allowing clinicians to form a hands-off, quick impression about whether the child is sick or not sick.
The triangle comprises three elements: A, B, and C, a mnemonic familiar to clinicians. But this ABC does not stand for airway, breathing, and circulation but instead translates to Appearance, work of Breathing and Circulation to the skin.
Appearance… Is the child interacting with caregivers and ambulance crew? Are they lethargic? Crying? Consolable? Limp in caregivers arms?
Work of Breathing… Are they using accessory muscles to help move air? Are they tripoding? Nasal Flaring? Are they breathing fast or slow? Can you hear a wheeze or stridor?
Circulation to the skin… Are they pale? Cyanotic? Mottled?
If all three parts of the triangle are normal, the child is likely to be stable. If all three parts of the triangle are abnormal, the patient is in cardio-respiratory failure.
Assessment of pain in the prehospital environment also poses different challenges to the evaluation in the hospital for the same reasons. We use the same age-appropriate pain scales as our hospital-based colleagues: FLACC, Wong-Baker and analogue pain scales. Clinical practice analgesia guidelines help direct medication choice, from simple painkillers such as paracetamol and ibuprofen to more potent analgesics like opiates and ketamine.
The ideal analgesic
The ideal properties of an analgesic are to provide effective pain relief rapidly, with painless administration. Gaining intravenous access in children can be challenging in the field, traumatic for children, and can delay the administration of analgesics. It can’t be stressed enough how important it is not to traumatise a child with cannulation when a good alternative is available. Intranasal fentanyl has had a significant impact on paediatric pain relief prehospital. In the UK, diamorphine is sometimes used instead of fentanyl; both are potent intranasal opioids rapidly and efficiently absorbed from the nasal cavity, giving significant potential for pain management in children.
Arriving at the house, you can hear a child crying; he’s maintaining his airway and is conscious. You make a snapshot PAT assessment: he’s stable. But his thigh is swollen, and it’s clear he’s fractured his femur. His parents have given him paracetamol and ibuprofen. Unfortunately, this one’s beyond the call of bubbles, so you put them away and instead draw up 0.02mg of fentanyl and give it intranasally.
The intranasal route
Analgesia can be given orally, rectally, intravenously, intramuscularly, or intranasally. Oral medications are metabolised via the hepatic first-pass pathway, meaning they are absorbed from the gastrointestinal tract and delivered first to the liver by the portal vein before reaching the systemic circulation, resulting in a relatively slow onset of action. Intranasal medications, on the other hand, are absorbed directly into the systemic circulation, bypassing hepatic first-pass metabolism. Hence, their bioavailability is higher, and their onset of action is much faster.
Because the nasal mucosa is highly vascularised, with more blood per cubic centimetre than muscle, brain or liver, with a surface area that’s massively increased by the three turbinates in each nostril (out pouches of bone inside the nostrils that create passageways that to warm and moisten the air that flows in through the nose), it is an ideal surface through which drugs with small molecular weights like fentanyl can be absorbed.
Once absorbed into the nasal blood vessels, drugs drain to the right side of the heart via the superior vena cava, are pumped into the pulmonary circulations, and then back through the left side of the heart to the systemic circulations.
Some intranasal drugs have an even faster mechanism of action. It’s thought that fentanyl, and other medicines with very small particle sizes, can also transfer directly to the brain via the olfactory and trigeminal nerves. This nerve superhighway means they can bypass the blood-brain barrier and work even faster at their central receptors in the brain.
The intranasal analgesic cavalry
Fentanyl is a synthetic opioid; diamorphine is a morphine derivative. As fentanyl doesn’t cause histamine release, it results in fewer cardiorespiratory side effects than other opiates. Both fentanyl and diamorphine can be safely combined with oral morphine, meaning intravenous morphine top-ups are less likely to be required. When given intranasally, their onset is within two to three minutes, with effects lasting up to half an hour. It’s easy to see how they’ve become a perfect choice for prehospital providers.
Ketamine, another analgesic in the prehospital analgesic armoury, can also be given intranasally, although it is not yet licensed via the intranasal route in children in the UK and Ireland. A few trials have compared intranasal ketamine and fentanyl, and there have been some exciting results, posing the question as to whether sub-sedative doses of intranasal ketamine could be used as an alternative analgesic for children with limb trauma.
Published in Annals of Emergency Medicine in 2014, the double-blinded RCT, PICHFORK (Pain In Children Fentanyl OR Ketamine), was run in two large Australian paediatric EDs.  Children aged 3 to 13 years old with moderate to severe pain secondary to an isolated limb fracture were randomized in a double-blinded fashion to receive either 1.5 μg/kg intranasal fentanyl or 1mg/kg intranasal ketamine. 73 children were included in the analyses. Similar reductions in pain scores were seen at 30 and 60 minutes for both drugs. The ketamine group had higher patient satisfaction scores (83% compared to 72% for fentanyl) but more minor adverse events (78% compared to 40% of the fentanyl group).
Published in 2017, a similar double-blinded RCT conducted in a level II trauma centre in America compared the two intranasal drugs at the same doses in 82 children aged 4 to 17. Like PICHFORK, their results showed more side effects in the intranasal ketamine group (2.2 times higher), but all were minor, with no respiratory adverse events. In addition, analgesic effects at 20 minutes were similar in both groups.
And finally, the PRIME (Pain Reduction With Intranasal Medications for Extremity Injuries) trial, a double-blinded RCT published in JAMA Pediatrics in 2019, showed similar results. 90 children, aged 8 to 17 years, presenting to a level I major trauma centre with limb trauma were randomized to receive either intranasal ketamine or fentanyl. Doses used were higher than those in standard clinical practice guidelines, with intranasal fentanyl dosed at 2μg/kg and intranasal ketamine at 1.5mg/kg. Like the other two trials, pain scores at 30 minutes were similar between both groups, while mild adverse events were found to be higher in the ketamine group (with a relative risk of 2.5), although again, all were transient.
So, is there a role for intranasal ketamine for children with isolated limb fractures in the prehospital or ED setting? None of these studies were powered to show a superiority of intranasal ketamine over fentanyl, but they do suggest that it’s non-inferior and a potential alternative. Although minor and transient, adverse events were higher in the ketamine groups, so it may not trump fentanyl as a first-choice analgesic. But for children in whom an opiate is contraindicated, intranasal ketamine might be an alternative. More data will be needed before intranasal ketamine makes its way onto standard CPGs; results from these trials are promising, with more extensive studies on the horizon.
After the intranasal fentanyl, the child settles. You apply traction to his leg, and with your colleagues’ help, you move him into an adult lower limb vacuum splint. This is a handy trick you’ve learned – the leg splint is just the right size to use as a whole body splint in small children, maintaining pelvic and spinal precautions. After moving to the back of the ambulance, he starts crying and is obviously in pain. You give him a second dose of 0.02mg fentanyl and phone medical support and discuss options with a senior clinician and get the go-ahead to give the third dose, en route to the hospital, if needed.
Ambulance control pre-alert the emergency department so they can prepare for an incoming paediatric trauma. The child’s mother sits next to the stretcher, holding his hand while you travel to the hospital. You explain to her what’s happened so far, what will you do if anything changes, and what might happen in the hospital. This calms her down. The child sleeps and that third dose of intranasal fentanyl is not required. As you pull onto the ambulance ramp he wakes. You hand him over to the waiting trauma team in resus; intravenous access is gained, IV morphine is given, and a Thomas Splint applied. After his primary survey is completed, an x-ray is taken, which confirms a femoral fracture.
The prehospital cannula
The question about intravenous access in the field is a tricky one. Inserting an IV line in a 2-year-old, particularly in the back of an ambulance, can be extremely difficult, and securing a cannula while travelling at speed requires the dexterity of a magician.
If intranasal medication is working, then there may not be a need for an IV line prehospital. This must always be balanced with the potential market for fluid resuscitation or other intravenous drugs. Each case is a judgment call based on the paediatric assessment triangle assessment and the need for intravenous medications. But never forget, if a child’s in pain and the bubbles don’t work, don’t forget the fentanyl.
You’re in the rapid response vehicle, having just handed over a 2 year old with a femoral fracture. As you clear the hospital, a call comes in: 8 year old, fall from slide, deformed left arm, conscious and breathing. When you arrive in the house you find him lying on the sofa, with bruising and deformity of his left elbow. The paracetamol and ibuprofen given by his mother has not controlled his pain*, so you take out a methoxyflurane inhaler and explain to him to suck in and blow out through ‘the whistle’. After a few breaths he begins to relax.
The inhaled route – methoxyfluarane
Methoxyflurane is a fluorinated hydrocarbon, used as an inhaled anaesthetic in the ’60s and early ’70s until it fell out of favour after case reports describing renal failure at anaesthetic doses. But, when given in small amounts, methoxyflurane has excellent analgesic properties with no nephrotoxic side effects.
It has been used extensively in Australia and New Zealand by prehospital clinicians as a self-administered analgesic for short-term pain relief in adults and children. After being licenced in 2015 in the UK and Ireland for the emergency relief of moderate to severe pain in conscious adults with trauma, methoxyflurane was included in the Irish prehospital CPG for EMTs, paramedics and advanced paramedics with permission under the seventh amendment to allow its use in children.
Added as a liquid to a Penthrox® inhaler, methoxyflurane vaporises to be inhaled on demand. It has revolutionised prehospital pain control due to its quick onset and easy, pain-free administration, and because of its lightweight, crews can carry it over rough ground easily. Known as ‘the green whistle‘, each 3ml dose is quoted to last between 20 and 30 minutes, but in practice can sometimes last up to 45 minutes or an hour, depending on a child’s respiratory rate and depth and how they self-administer.
The Irish prehospital CPGs allow two inhalers to be administered in 24 hours to a patient, so when there’s an extended journey time, methoxyflurane inhalers used back-to-back can provide up to two hours of analgesia, which can be supplemented by simple analgesics, paracetamol and ibuprofen, or morphine, fentanyl and ketamine, as needed.
But what’s the evidence for methoxyflurane in children?
Pop methoxyflurane in the PubMed search bar, and a lot comes up. It’s safe, it works, but there are surprisingly few randomised controlled trials (RCTs) that include children. A couple of observational studies are noteworthy. An Australian study in the prehospital setting, published in 2006 by Franz Babl and colleagues, describes an observational case series of 105 children, ranging in age from 15 months to 17 years, who received methoxyflurane while by being conveyed to hospital by ambulance. The children’s pain scores dropped from 7.9 to 4.5, with few side effects, although there was a tendency towards deep sedation in the under 5s.
The following year Babl’s team published an ED-based observational case series of 14 children aged 6 to 13 years with extremity injuries who received methoxyflurane for painful procedures in the hospital setting. Although methoxyflurane was a beneficial analgesic agent, Babl’s team found it did not work as well as procedural analgesia for fracture reduction.
Chin et al. published the first double-blind RCT of methoxyflurane in children almost two decades ago, in 2002. Forty-one children over the age of 5 with upper limb fractures were randomised to receive either methoxyflurane or a placebo. Unsurprisingly, methoxyflurane resulted in a lower pain score at 10 minutes than the placebo. Adverse events weren’t reported, but the apparent safety and efficacy of methoxyflurane demonstrated in this study paved the way for bigger and better RCTs.
A better known, and more recent, RCT involving children was the STOP! trial, published in the EMJ in 2014. This randomised, double-blind placebo-controlled trial was conducted at six EDs in the UK. Three hundred patients, 90 between the ages of 12 and 17, with minor trauma (such as burns, fractures, dislocations and lacerations), were randomised to receive either methoxyflurane or saline via an inhaler. In a nifty way to keep the patients, doctors and nurses blinded to which drug was being administered, a drop of methoxyflurane was added to the outside of every inhaler so both drug devices smelled the same. Pain scores dropped significantly lower in the methoxyflurane group, with a median onset of action of 4 minutes. But what about those adolescents? Although 45 12 to 17 year olds were included in each group, their data wasn’t analysed separately, and children under the age of 12 were excluded from the study, so although we can probably assume methoxyflurane works well and is safe in adolescents, more trials would be helpful.
Segue to the Magpie trial, which is currently recruiting in the UK and Ireland via the PERUKI network. This international multi-centre randomised, double-blind placebo-controlled trial is specifically investigating the efficacy and safety of methoxyflurane in children and young people so that its UK license can be extended to include children. Like STOP!, participants are being randomised to either methoxyflurane or placebo (again saline) via an inhaler. To ensure younger children are well represented in the study data, the study team are aiming to recruit higher numbers of 6 to 11 year olds than adolescents, with a recruitment target of 220 children and adolescents in total. We’re awaiting the results eagerly…
*A top tip on top up dosing
Before the crew arrived, his mother gave this child 500mg of paracetamol and 280mg of ibuprofen. He was eight years old, with an estimated weight of 31kg. Based on Irish CPGs allowing a paracetamol dose of 20mg/kg (620mg) and ibuprofen dose of 10mg/kg (310mg) he was underdosed. Using simple top-up analgesics is crucial as part of your approach to pain relief in children.
But what happened to the 8 year old?
You check CSMs (circulation, sensation and movement) before and after applying a splint and transfer him to the ambulance on a stretcher. His pain is very well controlled, and he asks his mother to take a photo for his friends. This sentence is hard for him to say, and he gets the giggles. You transfer him uneventfully to the hospital, where he’s diagnosed with a supracondylar fracture.
References
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Babl FE, Jamison SR, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas. 2006;18(4):404-410. doi:10.1111/j.1742-6723.2006.00874.x
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