Keeping it Peachy

Acute behavioural disturbance (ABD) includes agitation, violence, self-harm or delirium.

Acute Behavioural Disturbance is not a diagnosis or syndrome, but rather a clinical manifestation with diverse presenting characteristics and potential aetiologies.

It may result in risk of self-harm, harm to staff and to others and may require medical intervention to prevent this risk.

Generally, we try to start with non-pharmacological de-escalation techniques. When these techniques fail (and they sometimes will), what is the best oral medicine to help calm the distress?

The paper

Elyssia M. Bourke, Amit Kochar, Deborah Shellshear et al. PEAChY-O: Pharmacological Emergency Management of Agitation in Children and Young People: A Randomized Controlled Trial of Oral Medication. Annals of Emergency Medicine https://doi.org/10.1016/j.annemergmed.2025.01.007.

The PEAChY-O trial compared two widely used oral medications (olanzapine and diazepam) in the treatment of pediatric agitation.

Who were the patients?

Children and adolescents aged 9 to 17 years presenting to the emergency department (ED) with acute severe behavioural disturbance requiring oral medication after failed nonpharmacologic de-escalation.

They were randomised into the study if they had an initial agitation scale of +1 or greater based on the Sedation Assessment Tool.

What was the intervention?

Single dose of oral Olanzapine (5 mg if <40 kg, 10 mg if ≥40 kg), administered as a rapidly dissolving sublingual wafer.

Single dose of oral Diazepam (5 mg if <40 kg, 10 mg if ≥40 kg), administered in tablet form.

Doses based on existing literature referenced by the authors, and guideline from NSW government https://www1.health.nsw.gov.au/pds/ActivePDSDocuments/GL2015_007.pdf

By not using a mg / kg dosage, some patients may have been under dosed or over dosed relative to their weight.

What were the outcomes measured?

Primary outcomes:

Successful sedation (Sedation Assessment Tool score ≤ 0) without the need for additional sedatives at 1-hour post-randomisation.

What type of trial was this?

This was an open-label multicentre, randomised controlled trial.

What did they find?

There were a few differences between groups in any of the secondary outcomes.

The bottom line

Both oral olanzapine and diazepam were modestly effective 60% of the time with no serious adverse events.

There was a slightly higher proportion of patients who ingested Olanzapine (90%) compared to Diazepam (85%). This may be because olanzapine was given as a dissolving wafer and diazepam was a pill. The authors attribute to the ease of access of Olanzapine compared to diazepam in the ED in Australia (diazepam is a controlled drug in Australia).

CASP checklist – How good was the paper?

Does the study address a clearly focused issue?

Yes, there was a clear aim to determine whether oral olanzapine or oral diazepam was more effective in reducing ABD in young people aged 9 to 17 presenting to the emergency department.

Was the assignment of patients to treatment randomised?

Yes, the randomisation list was computer-generated by an independent statistician, on a 1:1 ratio between the two drugs. Using block randomisation, with variable blocks of 2, 4, and 6, stratified by site.

Were all the patients who entered the trial accounted for at its conclusion?

Yes, there were 348 participants, 176 patients were allocated to Olanzapine, and 172 to the diazepam group. A total of 22 patients across both groups had missing primary outcome data. Several patients in each group were randomised but did not ingest the medication.

A significant number of patients were eligible but not randomised (491 patients).

Were all patients, health workers and study personnel “blind” to treatment?

No. The study was open-label, meaning participants, parents, and clinicians knew the drug given. Diazepam is a controlled drug in Australia, and the medication was available in different compositions.

Were the groups similar at the start of the trial?

Unsure. Table 1 describes baseline characteristics of each group. There were slightly more participants in the olanzapine group who had received medication before presentation in the emergency department. The number of patients with autism spectrum disorder and ADHD was higher in the Olanzapine group.

Apart from the experimental intervention, did each study group receive the same level of care (that is they were equally treated)

Unsure. There is a degree of subjectivity in whether or not the treating clinician thought it was appropriate for the patient to receive an oral medication. We are also not sure of the extent or types of de-escalation that were attempted before medication administration.

The sedation assessment tool has shown good interrater validity in other studies, but there is still a degree of subjectivity. Some clinicians may say a patient is agitated, and another may say very agitated, giving different scores, although zero is calm, which is easier to score.

 Were the effects of intervention reported comprehensively?

Yes, there is a clear breakdown of results.

Although all participants had a Sedation Assessment Tool score of greater than 1 initially, the starting scores in the two groups were not equal (although close). It may have been easier to get from +1 to 0 than +3 to 0, which may have led to some bias in the groups. Four patients were administered diazepam when their SAT score had been recorded as being 0 (i.e. awake and calm/cooperative), and it is unclear why.

75% of staff completed the satisfaction surveys, which showed 64% satisfaction in the olanzapine group, and 56% satisfaction in the Diazepam group. Only around 20% of participants or caregivers completed their satisfaction surveys.

Was the precision of the estimate of the intervention or treatment effect reported?

Yes. The 95% confidence interval was adjusted for the risk difference, which ranged from -6.7% to 14%, not favouring either drug.

Notably, 13 patients had already had a sedative drug before they were given the trial drug, and the potential interaction of this is not discussed or considered.

Do the benefits of the experimental intervention outweigh the harms and costs?

Yes. Addressing ABD is essential for keeping patients, caregivers, and staff safe.

Adverse effects were reported, and there were no significant adverse effects, which included sedation-related adverse effects, extrapyramidal symptoms, and respiratory depression. Both medications were considered safe.

Can the results be applied to your local population/in your context?

Unsure. There is enormous variation in both national and international protocols for the management of paediatric ABD.

Clinicians should be familiar with their local protocols and the available medications. RCEM guidelines suggest oral lorazepam as a first-line agent. The two drugs were chosen after a survey of paediatric physicians found these to be the most used medications to treat ABD in Australia.

Would the experimental intervention provide greater value to the people in your care than any of the existing interventions?

No – The results showed no difference in the efficacy of the two medications.

What did the authors conclude, and what can we take away from this study?

It’s the first paper that we’ve got on the effectiveness of oral medications in paediatric ABD, and one of the first steps to getting a strong evidence base on the management of these complex patients.

We need to consider what the potential harms and benefits are of any medication.

There is no perfect one-size-fits-all medication for the management of paediatric ABD.

And finally, from the authors, Elyssia Bourke and Franz Babl

Paediatric acute severe behavioural disturbance is a high-risk condition which poses significant physical and psychological risk to the young person experiencing it and those caring for them. The ED is an increasingly common setting for young people to present when experiencing an episode of acute severe behavioural disturbance. Despite the urgency of this condition, there is currently little paediatric-specific evidence to guide non-pharmacological or pharmacological management. As a result, there is considerable variation in the management techniques used by clinicians when caring for these vulnerable young people.

The PEAChY-O study is the only randomised controlled trial to be published to date examining the use of oral sedatives for the management of paediatric acute severe behavioural disturbance in the ED setting. To our knowledge, it is actually the only trial to be published across any age group.

This was a challenging study to undertake as patients needed to be enrolled in a high-stress, time-critical situation by the treating clinician. More often than not, this meant enrolling the patient at 2 am in the ambulance corridor or whilst a security response (code grey/code black) was being enacted. A number of patients also took their own leave from the ED before their primary outcome was assessed, which again speaks to the challenges in providing clinical care to this cohort and undertaking research to improve the care provided to these patients. We are eternally grateful to all of the participating sites who embraced this work and recruited these patients to progress the evidence base for these young people.

The study team aimed to keep this trial as pragmatic and close to ‘real life’ conditions as possible. For this reason, we did not want to alter the physical presentation of the medications (diazepam – tablet; olanzapine – wafer) or offer a second ‘dummy’ placebo medication. The result of this was the study being open-label.

Pre-hospital sedative medication was not an exclusion criterion, as we felt the most important factor driving whether further sedative medication was provided in the ED was the young person’s current level of agitation, rather than what happened prior to their presentation.

We designed this study as an effectiveness study (intention to treat) to capture all events – such as refusal to ingest the study medication – which might occur between the clinician’s decision to administer an oral sedative and the participant’s ingestion of the medication. This was also a pragmatic decision by the study team. Our secondary efficacy analysis, which included only those patients who ingested the medication, mirrored the findings of our effectiveness analysis, though, revealing no statistical or clinical difference between study arms.

The most concerning finding for the study team from the PEAChY-O trial was that in 40% of cases, these medications failed to achieve behavioural containment. Additionally, in 15% of cases, aggression towards patients and/or staff was noted. Further research is required to identify a more effective oral sedative option to allow us to keep the young person and staff safe during these patient presentations. The PEAChY-O study team are currently determining which novel comparators should be considered for a follow-on study within this patient cohort.

Until further research is conducted, it appears that both oral olanzapine and diazepam are safe for use in the doses provided during our study and are probably equally effective. Clinicians can therefore select whichever medication they feel is most likely to be acceptable to the patient they are caring for until further research advancements are made within this important area.

References

SGEM #480 In the End It Doesn’t Even Matter: Oral Olanzapine or Diazepam for Pediatric Agitation

PEMCurrents: Pharmacologic Management of Agitated Children

emDocs: Agitation in Children

EMSC Agitation PEAK