Acute ingrijpmedicatie Medicamenteuze fixatie

Dr. Jürgen De Fruyt AZ Sint-Jan Brugge-Oostende AV Belangenconflict

Ik gaf in de voorbije drie jaar lezingen op symposia gesponsord door, woonde congressen bij gesponsord door, maakte deel uit van adviesorganen van: Janssen-Cilag. Acute ingrijpmedicatie

Historiek Acute ingrijpmedicatie/agitatie Klinische praktijk Farmacodynamische & -kinetische aspecten EBM Richtlijnen Varia Historiek

Opium, morfine, ether, chloroform, bromides (bromism, chloral hydraat (chloralism), cannabis, hyoscyamine/hyoscine, paraldehyde, …

FGA’s, benzodiazepines, SGA’s

Fennell, 1996

Medicamenteuze fixatie Acute ingrijpmedicatie/agitatie

Rapid neuroleptization Psychosis

Chemical restraint Violence

Urgent sedation Aggression

Rapid tranquillisation Agitation Acute ingrijpmedicatie

Controle van Controle van Behoud van respons gedrag stoornis

1-3 dagen weken/maanden maanden/jaren Acute ingrijpmedicatie/agitatie

Violence/aggression: a range of behaviours or actions that can result in harm, hurt or injury to another person, regardless of whether the violence or aggression is behaviourally or verbally expressed, physical harm is sustained or the intention is clear. NICE 2015 Psychomotor agitation: excessive motor activity with a feeling of inner tension. The activity is usually nonproductive and repititious and consists of behaviors such as pacing, fidgeting, wringing of the hands, pulling of clothes, and inability to sit still. APA, 2013 Agitation: motor restlessness, heightened responsivity to stimuli, irritability, inappropriate and/or purposeless verbal or motor activity, decreased sleep, fluctuation of symptoms over time. Lindenmayer, 2000 Agitation: a temporary disruption of the typical physician-patient collaboration, which interferes with assessment and treatment, during a period when immediate assessment and treatment are needed Allen, 2000 Acute ingrijpmedicatie/agitatie

Rapid tranquillisation: the use of medication to calm/lightly sedate the service user, reduce the risk to self and/or others and achieve an optimal reduction in agitation and aggression, thereby allowing a thorough psychiatric evaluation to take place, and allowing comprehension and response to spoken messages throughout the intervention. Although not the overt intention, it is recognised that in attempting to calm/lightly sedate the service user, rapid tranquillisation may lead to deep sedation/anaesthesia. NICE 2005

Rapid tranquillisation: the use of medication by the parenteral (usually intramuscular or exceptionally, intravenous, if oral medication is not possible or appropriate and urgent sedation with medication is needed. NICE 2015 Acute ingrijpmedicatie/agitatie

Agitatie & ED: Prevalentie 2,6% Delirium 23% Alcohol 83%, psychiatrisch 20%, middelen 12%, medisch 11% Mechanische fixatie 84%, RTIM 72%

Agitatie & psychiatrie: RTPO 50%, RTIM/IV 43%, RTPO+IM/IV 7%

Miner et al., 2018; POMH-UK, 2017 Klinische praktijk

Haloperidol 5mg/ml (Janssen-Cilag) Promethazine 50mg/2ml Droperidol 5mg/2ml (Prostrakan) Clotiapine 40mg/4ml (Juvise) Olanzapine 10mg (Eli Lilly) Lorazepam 4mg/ml (Pfizer) Midazolam (15mg/3ml) Klinische praktijk Klinische praktijk

Eerste keuze Tweede keuze Derde keuze Patiënten, niet in Olanzapine 22% Lorazepam 21% Clotiapine 19% afzondering

Patiënten, in Olanzapine 21% Droperidol 15% afzondering Clotiapine 21%

BervoetsBervoets et al., e.a. 2015, 2013 Farmacodynamische aspecten

Controle van gedrag

D2 Katalepsie

H1 Sedatie

5HT2a Antimanisch

Alpha1 Psycholepsie

GABA Sedatie Farmacokinetische aspecten

T-max (hr) T ½ (hr)

Haloperidol 2-6 24

Droperidol 1-2 2

Clotiapine ? 24-140

Risperidone * 1-2 20-30

Olanzapine 5-8 30

Quetiapine 1.5 6

Aripiprazole * 3-5 75

Lorazepam 2 12-16

Promethazine 3 9-16 EBM EBM

Clothiapine 2004 Olanzapine 2005 Haloperidol + promethazine 2009 Chloorpromazine 2010 Droperidol 2016 Haloperidol 2017 Benzodiazepines 2017 Risperidone 2018 Aripiprazole 2018

EBM

Olanzapine, haloperidol plus promethazine or droperidol are most effective and safe for use as rapid tranquilisation. Midazolam sedates most quickly. But due to increased saturation problems, midazolam is restricted to use within an emergency department of a general hospital. EBM

Veiligheid: - bewegingsstoornissen (EPS, dystonie, akathisie) - QTc verlenging - Hypotensie - Hypoventilatie - Sedatie Doeltreffendheid:

15-20 minuten 120 minuten

Haloperidol + promethazine 67-91% 89-97% Droperidol 53-92% Olanzapine 66% 73-91% Midazolam 55-89% 95% Lorazepam 78% 63-88% Traitement d’urgence de l’agitation : le droperidol (R4749). Acta Neurol Psychiatr Belg 1968; 68:103-15 Bobon et al.

Krachtige D2- en Alpha1-antagonist Janssen et al., 1961 Piek plasmaspiegels na ½-1 uur, halfwaardetijd ± 2 uur Sneller, doeltreffender en kortwerkender, minder toxisch dan haloperidol en chlorpromazine in dierexperimenteel onderzoek Induceert een toestand van rust en onthechting, afname van angst zonder bewustzijnsverlies. Populaire behandeling in anesthesie en psychiatrie

Black Box Warning 2001: QT-verlenging/TdP www.crediblemeds.org

Janssen, 1980; Chambers & Druss, 1999; Richards & Schneir, 2003 Droperidol – evidentie

8 RCT’s (7 dubbel-blind, 1 open): versus placebo, midazolam, lorazepam, haloperidol, ziprasidone, droperidol + midazolam 352 patiënten behandeld met droperidol (IM/IV) Doeltreffend bij 64-92%, binnen 30 minuten na toediening Trend van sneller effect dan haloperidol, ziprasidone en lorazepam Trend van iets trager maar meer voorspelbaar effect dan midazolam Snelle herevaluatie mogelijk Lage frequentie van bijwerkingen, weinig evidentie voor ernstige cardiovasculaire bijwerkingen Grote ecologische validiteit: spoedafdelingen, geen informed consent, hoge comorbiditeit Maar kleine patiënten aantallen, beperkte uitkomstmaten m.b.t. doeltreffendheid (bv. agitatie, sedatie) en veiligheid, …

BudihartoBudiharto & De & Fruyt,De Fruyt, 2013 2013 Le contrôle chimique de l’excitation aiguë et de l’agitation par clotiapine injectable (II). Revue Médicale de Liège 1973; 83-87. Collard et al.

In jaren ‘60 ontwikkeld door Wander

2-chloro-11-(4-methyl-1-piperazinyl)-dibenzo-(b,f)(1,4)-thiazepine - dibenzothiazepine antipsychoticum

Atypisch antipsychoticum ‘avant la lettre’, cf. clozapine

Werking in drie fases: angst werend, sedatief en antipsychotisch?

Farmacokinetiek en metabolisme niet goed gekend?

Lange Belgische ervaring in de behandeling van patiënten met een psychotische stoornis en geagiteerde patiënten. Clotiapine – evidentie

2 RCT’s (dubbel blind, gerandomiseerd): versus zuclopenthixol acetaat en lorazepam.

51 (op 102) patiënten behandeld met IM clothiapine

Gebrekkige rapportage van doeltreffendheid en veiligheid

Even doeltreffend als lorazepam, minder EPS?

Onvoldoende en niet conclusieve evidentie…

Claeys et al., 2017 Richtlijnen

Bak e.a. (2011) – Acute ingrijpmedicatie: Niet psychotische agitatie: lorazepam 2-4mg Psychotische agitatie: haloperidol 5-10mg + promethazine 25-50mg, olanzapine 10-20mg

NICE (2015) – Short term management of violence and aggression

WFSBP (2016) – Assessment and management of agitation

BAP NAPICU (2018) – Clinical management of acute disturbance

NICE

•Rapid tranquillisation in this guideline refers to the use of medication by the parenteral route (usually intramuscular or, exceptionally, intravenous) if oral medication is not possible or appropriate and urgent sedation with medication is needed. •1.4.37 Use either intramuscular lorazepam on its own or intramuscular haloperidol combined with intramuscular promethazine for rapid tranquillisation in adults. When deciding which medication to use, take into account: •the service user's preferences or advance statements and decisions •pre-existing physical health problems or pregnancy •possible intoxication •previous response to these medications, including adverse effects •potential for interactions with other medications •the total daily dose of medications prescribed and administered. NICE

•1.4.38 If there is insufficient information to guide the choice of medication for rapid tranquillisation, or the service user has not taken antipsychotic medication before, use intramuscular lorazepam.

•1.4.39 If there is evidence of cardiovascular disease, including a prolonged QT interval, or no electrocardiogram has been carried out, avoid intramuscular haloperidol combined with intramuscular promethazine and use intramuscular lorazepam instead. NICE

•1.4.40 If there is a partial response to intramuscular lorazepam, consider a further dose.

•1.4.41 If there is no response to intramuscular lorazepam, consider intramuscular haloperidol combined with intramuscular promethazine.

•1.4.42 If there is a partial response to intramuscular haloperidol combined with intramuscular promethazine, consider a further dose. NICE

•1.4.43 If there is no response to intramuscular haloperidol combined with intramuscular promethazine, consider intramuscular lorazepam if this hasn't been used already during this episode. If intramuscular lorazepam has already been used, arrange an urgent team meeting to carry out a review and seek a second opinion if needed.

•1.4.44 When prescribing medication for use in rapid tranquillisation, write the initial prescription as a single dose, and do not repeat it until the effect of the initial dose has been reviewed. NICE

Monitoren van: SE HF, BD, AF, T, hydratatie & bewustzijn Om de 60 minuten! Om de 15 minuten! Wanneer maximum dosis overschreden. Indien patiënt slaapt, sedatie, inname alcohol of illegale middelen, somatische problematiek…

Plaats van ECG voor en na RT? Haloperidol, droperidol, olanzapine… WFSBP

Agitation with no provisional diagnosis or with no available information should be presumed to be from a general medical condition until proven otherwise.

The routine medical examination in an agitated patient should include a complete set of vital signs, blood glucose measurement (finger stick), determination of oxygenation level, and a urine toxicology test.

After treating agitation, systematic assessment of sedation levels should be performed.

WFSBP

The main goal of pharmacological treatment should be to rapidly calm the agitated patient without over-sedation.

Agitated patients should be as much as possible involved in both the selection of the type and the route of administration of any medication.

When planning involuntary pharmacological treatment team consent should be reached and the action carefully prepared.

Oral medications, including solutions and dissolving tablets, should be preferred to intramuscular route in mildly agitated patients. WFSBP

A rapid onset of the effect and the reliability of delivery are the two most important factors to consider in choosing a route of administration for the treatment of severe agitation.

In the case of agitation secondary to alcohol withdrawal treatment with benzodiazepines should be preferred over treatment with antipsychotics.

In the case of agitation associated with alcohol intoxication, treatment with antipsychotics should be preferred over treatment with benzodiazepines.

In mild-to-moderate agitation, and when rapid effects of medication are needed, inhaled formulations of antipsychotics may be considered. WFSBP

The concomitant use of intramuscular olanzapine and benzodiazepines should be avoided, due to the possible dangerous effects induced by the interaction of the two medications in combination (hypotension, bradycardia, and respiratory depression).

Intravenous treatment should be avoided except in cases where there is no alternative.

Elderly agitated patients should be treated with lower doses: usually between a quarter and a half of the standard adult dose. BAP NAPICU BAP NAPICU * Bij geen effect, op geleide van het beeld vaker en met hogere dosis herhalen, gelet op verdelingsvolume en leeftijd. Houd rekening met mogelijke kruistolerantie benzodiazepines en alcohol

** Haloperidol/promethazine: bij onvoldoende effect na 30 min. tot 1 uur: haloperidol niet herhalen, maar 25-50 mg promethazine geven als monotherapie per 30 min. Indien geen haloperidol met promethazine is gebruikt: lorazepam 1-2 mg oraal of parenteraal toevoegen, cave min. 2 uur voor/na olanzapine i.m. Van Gelder et al., 2017 Ouderen > 65 jaar en/of bij hersenbeschadiging

Algemeen: Haloperidol 2 mg (max. 5 mg/24 u ) + eventueel promethazine 25 mg (promethazine liever vermijden bij ouderen en delirante patiënten in verband met sterke anticholinerge eigenschappen); Cave: valgevaar bij ouderen na ingrijpmedicatie. Dementie met uitzondering van ‘Lewy body’-dementie: Bij voorkeur niet medicamenteus behandelen. In principe is haloperidol met promethazine mogelijk (zie voor dosering hierboven). Alternatief: olanzapine 2,5-5 mg per os maximaal 10 mg /24 uur; olanzapine 2,5 i.m., herhalen per 30 min., maximaal 7,5 mg /24 uur. ‘Lewy body’-dementie en ziekte van Parkinson: Lorazepam 0,5-1 mg per os/ 0,5-1 mg i.m. Géén antipsychotica met uitzondering van clozapine (12,5-50 mg) en quetiapine (25-100 mg). Bij bekende hersenbeschadiging en andere organische oorzaken: Antipsychotica en benzodiazepines relatief gecontra-indiceerd. Overweeg: diagnosespecifieke farmacologische behandeling.* Indien noodzakelijk: haloperidol 2 mg (max. 5 mg/24 u ) + promethazine 25 mg.**

* Agitatie ten gevolge van een organische, intracerebrale oorzaak (tumor, trauma, hersenbeschadiging anderszins) vraagt om een diagnosespecifieke farmacologische behandeling conform de desbetreffende evidentie, zoals behandeling met bètablokkers of carbamazepine bij traumatisch letsel. Benzodiazepines zijn in deze gevallen relatief gecontra-indiceerd op grond van het induceren van (verdere) bewustzijnsdaling en mogelijke toename van agitatie ** Haloperidol/promethazine: bij onvoldoende effect na 30 min. tot 1 uur: haloperidol niet herhalen, maar 25-50 mg promethazine toevoegen, per 30 min. Van Gelder et al., 2017 Excited delirium

Agitated delirium/sudden death in custody ‘Bell’s mania’ Bv. drug intoxicatie + mentale stoornis + politionele interventie + RT (+ ECD) + plotse dood Delirium + extreme agitatie + hyperthermie, acidose, rhabdomyolyse, hyperkaliëmie Vilke et al., 2012 Nood aan snelle interventie: Intensieve Zorgen Sedatie met benzodiazepine, antipsychotica, ketamine, clonidine, dexmedetomidine… Toxidromen

Demping: alcohol, benzo’s, opioïden, GHB

Sympathicomimetisch: cocaïne, amfetamines

Hallucinatoir: cannabis, LSD, PCP, ketamine

Serotonerg: antidepressiva, morfine

Anticholinerg: scopolamine, quetiapine

Medische screening! Literatuur

Violence and aggression: short-term management in mental health, health and community settings. NICE guideline [NG10] Bak M, Weltens I, Bervoets C, De Fruyt J, Samochowiec J, Fiorillo A, Sampogna G, Bienkowski P, Preuss WU, Misiak B, Frydecka D, Samochowiec A, Bak E, Drukker M, Dom G. The pharmacological management of agitated and aggressive behaviour: A systematic review and meta-analysis. Eur Psychiatry. 2019 Apr;57:78-100. Claeys J, Bervoets C, De Fruyt J. [Clotiapine in the treatment of acutely agitated patients: hardly any evidence]. Tijdschr Psychiatr. 2017;59(3):175-180. Bervoets C, Roelant E, De Fruyt J, Demunter H, Dekeyser B, Vandenbussche L, Titeca K, Pieters G, Sabbe B, Morrens M. Prescribing preferences in rapid tranquillisation: a survey in Belgian psychiatrists and emergency physicians. BMC Res Notes. 2015 Jun 5;8:218. Budiharto L, De Fruyt J. [Droperidol for the treatment of acutely agitated patients: still an option]. Tijdschr Psychiatr. 13;55(3):183- 92. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vázquez G, Baldaçara L, San L, McAllister-Williams RH, Fountoulakis KN, Courtet P, Naber D, Chan EW, Fagiolini A, Möller HJ, Grunze H, Llorca PM, Jaffe RL, Yatham LN, Hidalgo-Mazzei D, Passamar M, Messer T, Bernardo M, Vieta E. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17(2):86-128. Patel MX, Sethi FN, Barnes TR, Dix R, Dratcu L, Fox B, Garriga M, Haste JC, Kahl KG, Lingford-Hughes A, McAllister-Williams H, O'Brien A, Parker C, Paterson B, Paton C, Posporelis S, Taylor DM, Vieta E, Völlm B, Wilson-Jones C, Woods L; With co-authors (in alphabetical order):. Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: De-escalation and rapid tranquillisation. J Psychopharmacol. 2018 Jun;32(6):601-640.