Rapid Tranquillisation
‘Rapid tranquillisation’ refers to the use of
medi-cation to calm highly agitated individuals
experi-encing mental disorder who have not
responded to non-pharmacological approaches.
Commonly it is the initial stage in the treatment
of severe and enduring illness.
It is commonly the initial stage in the treatment of a
first or recurrent episode of severe mental illness, and
is followed by treatment to reduce other symptoms,
leading to remission and prevention of relapse.
The disorders involved are usually affective disorders
or schizophrenia (Pilowsky 1992), often complicated
by substance misuse and personality disorder.
Agitation and arousal can lead to aggression and
violence
Learning objectives
Recognise the role of brain transmitter path-ways leading to
arousal and to agitation
Be aware of mechanisms of action of benzodia-zepines,
antipsychotics and antihistamines and distinguishing
sedation from calming effects
Know the recommendations of NICE guidelines for rapid
tranquillisation and the findings of the national POMH-UK
audit and be able to con-tribute to local policies
Aims of Rapid tranquillisation
History
A traditional way of coping with the violence of the mentally ill
was by physical restraint.
early 19th century in England, came the demonstration that
calm, friendly concern for the individual and simple
psychological management made much of restraint unnecessary.
With the advent of drug treatments, bromides, chloral, hyoscine,
paraldehyde, morphine, and later barbiturates, became the
compellers of peace, in effect, by heavy sedation, or partial
anaesthetisation or in some cases by inducing a
toxic-confusional state (Shorter 1997).
Current services
Modern psychotropics with more subtle effects calm without
necessarily making the person unconscious or even unduly
drowsy, and psychological handling remains an important
component of management (McLaren 1990).
Since 1985, many in-patient services have created psychiatric
intensive care units (PICUs)
the PICUs have found it increasingly necessary to use restraint and
seclusion once again.
The timely use of effective tranquillisation should reduce this: PRN
medication should be used to de-escalate or prevent agitation
Neurochemical pathways in arousal and agitation
Arousal
A
The most common neurotransmitters in the brain
glutamate (excitatory)
gamma-aminobu-tyric acid (GABA) (inhibitory).
These are very widely distributed
There are small sets of neurons utilising other transmitters -noradrenaline(NA), dopamine (D), histamine (H), acetylcholine (ACh) and serotonin or5-hydroxytryptamine (5-HT).
Other transmitters known to be involved in arousal are
orexin (which is blocked by the drug suvorexant)
adenosine (which is blocked by caffeine)
B
Wakening -a signal from the serotonergic suprachiasmatic
nucleus (‘the biological clock’) activates orexin neurons in
the hypothalamus, which cause firing of sets of histamine
neurons (in the tuberomamillary nucleus), nor adrenaline
neurons (including those of the nucleus locus ceruleus)
and acetylcholine neurons of the pontine reticular
formation. This corresponds to the awake, alert or aroused
state
C
A more frontal acetylcholine pathway from the nucleus
basalis of Meynert to the cerebral cortex is involved in
attention, concentration and memory
D
By contrast, the deep sleeping state (slow wave sleep)
involves diminished release of orexin, histamine,
noradrenaline and acetylcholine. Rapid eye movement
(REM) sleep (dreaming) involves activation of nicotinic
acetylcholine receptors via the pontine reticular
formation
E
Another feature of arousal is activation of dopamine
neurons, which have the role of drawing attention to
significant sensations or experiences, causing alertness
(Schultz 1997) and signalling motivational salience, which
may be incentive or aversive.
Agitation
Anxiety and agitation are commonly attributed to excessive
arousal through increased noradrenergic and reduced
serotonergic function.
It has been found that dopamine release in basal ganglia
regions is increased in first-episode patients with psychotic
mania as well as in those with schizophrenia.
Assessing the patient
know the patient’s medication history and whether agitation is
occurring in the context of physical illness, mania, paranoid
psychosis, delirium or drug intoxication.
to read previous notes and listen to what the patient says: this
may sometimes be strongly personalised and threatening but
nonetheless revealing.
An electro-cardiogram (ECG) is a prudent investigation for
all psychiatric admissions, or a note of its refusal.
Drug treatment in Rapid tranquillisation
If violent or disturbed behaviour continues or is threatened, it
may need to be controlled rapidly.
The aim of rapid tranquillisation is to calm or sedate the
patient sufficiently to minimise the risk posed to the patient
and to others.
Sometimes it addresses also the underlying illness, particularly
mania, which can improve with non-sedative antipsychotics
within minutes or hours .
Improvement in agitation can be seen much sooner.breakdown
benzo 8
egs
MOA
effects
Routes IM
haloperidol side effects
2 combination
sudden death
BNF recommendations for halo
3 other IM
2 other
anticholinergics
anti histamines
others 2
TREC
Classes of drugs
Neurochemical basis of drug treatments for agitation
Glutamate transmission has not yet proved an effective target
in rapid tranquillisation, although ketamine, which blocks
N-methyl-D-aspartate-sensitive glutamate receptors
(NMDAR), is a general anaesthetic agent and has a rapid
effect, reducing suicidal ideation and improving mood in
severe depression within 1 h, which midazolam does not
The locus ceruleus projects to the medial septal area and
cortex through alpha-1 and beta receptors to cause arousal
(Berridge 2012). Noradrenergic alpha-1 receptors are of three
subtypes, alpha-1B being involved in the central nervous
system.
In the human iris, alpha-1 re-ceptors are blocked by therapeutic
doses of haloperi-dol (Szabadi 1981). This action could
contribute to the beneficial effects of haloperidol,
zuclo-penthixol, olanzapine and chlorpromazine – seda-tive
antipsychotics.
Table 2 shows the relative potencies of antipsy-chotics and
promethazine in blocking receptors and in causing QT
prolongation by blocking the IKr cardiac potassium channels
also known as hERG channels (see ‘Antipsychotics, cardiac
con-duction and sudden death’ below).
To reduce agitation further it is it is necessary to address the
underlying condition (e.g. schizophre-nia, mania) by reducing
dopamine function.
Benzodiazepines 8
If there is uncertainty about the diagnosis, it may be
desirable to use benzodiazepines initially and to avoid the
use of antipsychotic drugs; this would apply with catatonia
where neuroleptic malignant syndrome is a particular risk
(Sienaert 2014).
Table 3 shows the different potencies, rates of absorption
and onset, and duration of action.
For oral use diazepam or clonazepam may be given, and for
intramuscular use lorazepam.
Antipychotics
major tranquillisers
The effects occur within minutes of drug delivery and generally more
quickly with parenteral than oral routes. Antipsychotics available for
intramuscular use in the UK are haloperidol, olanzapine, aripiprazole
and chlorpromazine.
It lacks anti-histaminergic and anticholinergic activity, but blocks
noradrenergic alpha-1 receptors.
The side-effects of haloperidol are particularly the extrapyramidal ones
– Parkinsonism, dystonia and akathisia. A Cochrane review on the
drug states that ‘Where additional drugs are available, sole use of
haloperidol for extreme emergency could be considered unethical’
It is therefore advisable to consider administering an anticholinergic
drug together with haloperidol to prevent dystonia. In the treatment of
schizophrenia
Combined antipsychotic and benzodiazepine
This combination engages different mechanisms of
action in the expectation of mutual augmentation
while avoiding complications from higher doses of
antipsychotics.
Antipsychotics, cardiac conduction and sudden death
Several factors contribute
ability of drugs to enter the potassium channels that open during
the cardiac action potential (the IKr or hERG channel: Box 2);
this delays repolarisation, leading to prolongation of the QT
interval, a factor predisposing to ventricular tachycardia
(torsades de pointes) and hence to ven-tricular fibrillation and
death.
Prolongation of the QT interval is thus a surrogate marker
for drug-related cardiotoxicity, albeit a weak one.
Interpretation of the QT interval is difficult if the pulse rate
is increased
haloperidol has attracted most concern, because it has been
used in high doses parenterally for rapid tranquillisation
Changes in BNF recommendation for haloperidol
From 1988 to 2000, the British National Formulary (BNF)
recommended a maximum haloperidol intra-muscular dose of 30 mg
followed by 5 mg up to every hour. However, nurses would not want
to enter a seclusion room every hour. Over the past 30 years there have
been dramatic changes in the advised doses of haloperidol – most
notably since 2000 (Table 5). These changes reflect concerns about
potential cardiac side-effects of the drug (in high doses) as well as a
lack of evidence for greater efficacy with higher doses in the control of
symp-toms of schizophrenia. There is now a requirement for an ECG
in any patient before administration of haloperidol. Intravenous use of
haloperidol is no longer licensed or recommended, owing to a greater
adverse effect on cardiac conduction.
suggesting that at doses up to 15 mg/day the change in QTc
with haloperidol was no greater than with placebo.
The International Conference on Harmonisationa (ICH)
stated that ‘drugs that prolong the mean QT/ QTc interval by
>20 ms have a substantially increased likelihood of being
proarrhythmic’
Other antipsychotics
Zuclopenthixol
Zuclopenthixol is more sedative than haloperidol and does not
prolong the QT interval
effect lasting for about 3 days.
The onset of action takes 2–8 h. Maximum serum concentrations
of zuclopenthixol are usually reached 36 h after an injection, so
that side-effects may be delayed. With up to four doses,
zuclopenthixol acetate may maintain improvement for 2 weeks.
With the final dose, the longer-acting zuclo-penthixol decanoate
may also be given. It has a dur-ation of 1–2 weeks and peak plasma
concentrations are usually reached between 4 and 7 days after
injection.
Chlorpromazine
a sedative antipsychotic
may be given orally as tablet or syrup.
may also be given by intramuscular injection
can cause local pain, acute hypotension and occasionally a
painful sterile abscess.
has a higher risk of inducing seizures.
For these reasons chlorpromazine should not be the
first-line treatment, and some authorities avoid its use.
Newer antipsychotics for IM use
Olanzapine
Olanzapine 10 mg is as effective in reducing agita-tion in
schizophrenia as 7.5 mg haloperidol over the course of 2 h,
although a benefit is seen within 15 min with olanzapine and
within 30 min with haloperidol (Wright 2001).
Also effective in reducing agitation in mania over 2 h
The manu-facturer Lilly stopped promoting its intramuscular
use in the UK and it is no longer in the BNF – its use is now
off-licence.
It should not be administered simultaneously with
benzodiazepines (Lilly 2018).
Aripiprazole
Aripiprazole given intramuscularly improves
mod-erately severe agitation in schizophrenia over 2 h.
Loxapine
by nasal inhalation
Inhaled loxapine 5–10 mg pro-duces significant
improvement in agitated patients with schizophrenia
or mania, from 10 min.ANTICHOLINERGICS
Today, anticholinergics are used only to counteract
extra-pyramidal (Parkinsonian) side-effects.
Procyclidine and, to a greater extent, benzhexol have
stimulant properties.
ANTIHISTAMINES
During the 1940s the pharmaceutical industry developed drugs
that block histamine; they were used for allergic conditions,
but had sedative side-effects and were tried in psychiatric
patients
The French anaesthetist and explorer Henri Laborit included
promethazine with pethidine and other agents in what he
called a ‘lytic cocktail’ to assist in anaesthesia.
Delay and Deniker were impressed by the difference between
chlorpromazine and antihistamines for calming schizophrenia
and mania.
Histamine was established as a central neuro-transmitter in
1984
TREC studies
The Tranquilização Rápida-Ensaio Clínico (rapid
tranquillisation clinical trial, TREC)
These compared the use of promethazine (25 or 50 mg)
in combination with haloperidol (5 or 10 mg) with four
different comparators (midazolam, lorazepam,
haloperidol alone and olanzapine). The combination was
being used as a cheap alternative to lorazepam and to
atypical antipsychotics.
They demonstrated the relative safety of the com-bination,
with a low incidence of extrapyramidal side-effects, but the
speed of tranquillisation (number calmed or asleep within 30
Other sedatives
The barbiturate amobarbital sodium (sodium
amy-lobarbitone, sodium amytal) (250 mg) given
intramuscularly as an adjunct to sedative
antipsy-chotics and benzodiazepines can be very
effective for sedation.
min) was less than with midazolam.
Other antimania drugs
Valproate is recommended (usually in combination
with antipsychotics) in guidelines as a first-line
treat-ment for mania (Goodwin 2016)
Curiously, the sedative effect of the combination was more
apparent in India than in Brazil, perhaps because the higher
dose of haloperidol was consistently used
GUIDELINES AND POLICIESentire process
3 modes
6 points of drugs
site
volume
monitoring
refuse
Medication specific risk
CG 25 (7)
NG10 (10)
CG25 (National Collaborating Centre for Nursing and
Supportive Care 2005), has now been withdrawn and replaced
with the second, NG10 (National Collaborating Centre for
Mental Health 2015).
However, the lessons from years of use and individual trials
can be lost in the proces
For rapid tran-quillisation many protocols recommend doses
according to the BNF, and advice on what to do if these are to
be exceeded.
previous NICE guidance: CG25
for those who are not psychotic, initially give lorazepam alone
(1.8.4.10)
in those with psychosis, use a combination of an oral antipsychotic
with lorazepam (1.8.4.11)
where oral medication is not possible, use combined intramuscular
antipsychotic and benzodiazepine (e.g. haloperidol and lorazepam)
(1.8.4.15)
CG25 also notes that:
the intramuscular route is preferred over the intravenous route
(1.8.4.14)
with intramuscular haloperidol, an antimuscari-nic drug such as
procyclidine should be immedi-ately available and given
intramuscularly or intravenously (1.8.4.21)
CG25 also notes that:
there was deemed to be insufficient safety evi-dence for the use of
intramuscular combined halo-peridol plus promethazine, or for the
use of intramuscular midazolam (1.8.4.17), although these could be
used as alternatives ‘in very excep-tional circumstances’, as could
intravenous ben-zodiazepines or haloperidol (1.8.4.22)
zuclopenthixol acetate injection may be consid-ered as an option, but
is not recommended (1.8.4.26) and is ‘not normally used (p.139).
Further considerations in CG25
It was recognised (1.8.4.27 and 1.8.4.28) that clinicians sometimes
use medication for rapid tran-quillisation outside the limits indicated
in the BNF
However, it was advised that, where the regulatory authority or
manufacturer warns of increased risk of fatality, medication should
be used within the marketing authorisation.
Current NICE guidance: NG10
Limitations of NG10
However, in NG10 rapid tranquillisation refers only to the use of
medication parenterally (8.4.7).
The guidance refers to violence, but there is no consideration of the
context in which it occurs and no mention of diagnosis.
There is no reference to treatment of schizophre-nia, mania or
delirium, although ‘staff should be trained to recognise them’ (1.5.5).
Medications that are not mentioned at all include: diazepam,
midazolam, clonazepam, chlorpromaz-ine, clopenthixol, aripiprazole,
loxapine, anticholi-nergics, procyclidine, lithium and valproate (the
last of which is so useful in acute psychotic mania both alone and as
an adjunct to antipsychotics).
Recommendations on rapid tranquillisation in NG10
use either intramuscular lorazepam alone or intramuscular haloperidol with promethazine (6.6.3.21)
if there is no recent satisfactory ECG, avoid intra-muscular haloperidol with promethazine and use intramuscular lorazepam (6.6.3.23), and if the response is partial consider a further dose (6.6.3.24)
if there is no response to intramuscular loraze-pam, consider intramuscular haloperidol with promethazine (6.6.3.25), and if there is partial response consider a further dose (6.6.3.26); this implies overruling the BNF advice on the need for an ECG
if there is no response to intramuscular haloperi-dol with promethazine, consider intramuscular lorazepam if not already used (6.6.3.27)
if intramuscular lorazepam has already been used, arrange an urgent team meeting to review and seek a second opinion if needed (no sugges-tionsare offered of what the second opinion might advise).
NG10 also recommends that:
a senior doctor should review all medication at least once a day
(5.7.1.17)
the multidisciplinary team should review the pharmacological
strategy at least once a week (details about this review are provided).
GUIDELINES
>Ensure procyclidine injection is available. Antipsychotics may cause acute dystonic reaction.
>Ensure flumazenil injection is available to reverse effects of lorazepam injection.
> NICE guideline NG10 does not include the use of olanzapine IM injection as there is no UK product available, having been withdrawn from the UK market. However BAP 2018 stated that IM olanzapine is effective and therefore is included in the algorithm
> Promethazine has anticholinergic side effects such as dry mouth, blurred vision, urinary retention and constipation. Cognition can also be impaired particularly in patients with a diagnosis of dementia. It should therefore be used with caution in this patient group
> It should be noted that antipsychotics in RT are not used for their antipsychotic action as onset of the antipsychotic effect can take several weeks.
>If haloperidol is used when no ECG is available the prescriber should consider the risks and benefits of using this treatment and be able to justify their prescribing decision as this would be considered an ‘off-label use’
> Medicines for injection must not be mixed in the same syringe.
>
>
> 1 If the patient refuses / declines monitoring ‘R’ for refusal should be endorsed on the chart. As a minimum respiration rate and level of consciousness using the “alert, voice, pain, unresponsive” (AVPU) system must be recorded. This would include patients held in seclusion
Youtube
Inject or take oral and then wait till he calms down before proceeding.
Otherwise have to use restraint to allow him to take.
Bare in mind the DDs
Collateral information or history is important
toxic dromes as in sympathetic, cholinergic and serotonergic signs
Then specific treatment
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